The past 25 years have seen enormous progress in the deciphering of the genetic and molecular bas... more The past 25 years have seen enormous progress in the deciphering of the genetic and molecular basis of ataxias, resulting in improved understanding of their pathogenesis. The most significant milestones during this period were the cloning of the genes associated with the common spinocerebellar ataxias, ataxia telangiectasia, and Friedreich ataxia. To date, the causative mutations of more than 30 spinocerebellar ataxias and 20 recessive ataxias have been identified. In addition, there are numerous acquired ataxias with defined molecular causes, so that the entire number of distinct ataxia disorders exceeds 50 and possibly approaches 100. Despite this enormous heterogeneity, a few recurrent pathophysiological themes stand out. These include protein aggregation, failure of protein homeostasis, perturbations in ion channel function, defects in DNA repair, and mitochondrial dysfunction. The clinical phenotypes of the most common ataxia disorders have been firmly established, and their natural history is being studied in ongoing large observational trials. Effective therapies for ataxias are still lacking. However, novel drug targets are under investigation, and it is expected that there will be an increasing number of therapeutic trials in ataxia. V
The spinocerebellar ataxias (SCAs) comprise more than 40 autosomal dominant neurodegenerative dis... more The spinocerebellar ataxias (SCAs) comprise more than 40 autosomal dominant neurodegenerative disorders that present principally with progressive ataxia. Within the past few years, studies of pathogenic mechanisms in the SCAs have led to the development of promising therapeutic strategies, especially for SCAs caused by polyglutamine-coding CAG repeats. Nucleotide-based gene-silencing approaches that target the first steps in the pathogenic cascade are one promising approach not only for polyglutamine SCAs but also for the many other SCAs caused by toxic mutant proteins or RNA. For these and other emerging therapeutic strategies, wellcoordinated preparation is needed for fruitful clinical trials. To accomplish this goal, investigators from the United States and Europe are now collaborating to share data from their respective SCA cohorts. Increased knowledge of the natural history of SCAs, including of the premanifest and early symptomatic stages of disease, will improve the prospects for success in clinical trials of disease-modifying drugs. In addition, investigators are seeking validated clinical outcome measures that demonstrate responsiveness to changes in SCA populations. Findings suggest that MRI and magnetic resonance spectroscopy biomarkers will provide objective biological readouts of disease activity and progression, but more work is needed to establish disease-specific biomarkers that track target engagement in therapeutic trials. Together, these efforts suggest that the development of successful therapies for one or more SCAs is not far away. The spinocerebellar ataxias (SCAs) are a group of autosomal dominant disorders characterized by progressive ataxia due to degeneration of the cerebellum and its afferent and efferent pathways 1 . The prefix 'SCA' with an associated number (which reflects the order of genetic discovery) is assigned to dominantly inherited ataxias when their genetic loci are defined. Although the term SCA describes a broad category of disorders in which *
Huntington's Disease (HD) is caused by a CAG repeat expansion that encodes a polyglutamine (polyQ... more Huntington's Disease (HD) is caused by a CAG repeat expansion that encodes a polyglutamine (polyQ) expansion in the HD disease protein, huntingtin (HTT). PolyQ expansion promotes misfolding and aggregation of mutant HTT (mHTT) within neurons. The cellular pathways, including ubiquitin-dependent processes, by which mHTT is regulated remain incompletely understood. Ube2W is the only ubiquitin conjugating enzyme (E2) known to ubiquitinate substrates at their amino (N)-termini, likely favoring substrates with disordered N-termini. By virtue of its N-terminal polyQ domain, HTT has an intrinsically disordered amino terminus. In studies employing immortalized cells, primary neurons and a knock-in (KI) mouse model of HD, we tested the effect of Ube2W deficiency on mHTT levels, aggregation and neurotoxicity. In cultured cells, deficiency of Ube2W activity markedly decreases mHTT aggregate formation and increases the level of soluble monomers, while reducing mHTT-induced cytotoxicity. Consistent with this result, the absence of Ube2W in HdhQ200 KI mice significantly increases levels of soluble monomeric mHTT while reducing insoluble oligomeric species. This study sheds light on the potential function of the non-canonical ubiquitin-conjugating enzyme, Ube2W, in this polyQ neurodegenerative disease.
Accumulation of mutant polyglutamine proteins in intraneuronal inclusions is a hallmark of polygl... more Accumulation of mutant polyglutamine proteins in intraneuronal inclusions is a hallmark of polyglutamine diseases. Impairment of protein clearance systems and sequestration of clearancerelated proteins into inclusions occur in many protein folding diseases, including the polyglutamine diseases. The ubiquitin-binding and proteasome adaptor protein UBQLN2 participates in protein homeostasis and localizes to inclusions in various neurodegenerative diseases. Employing mouse models and human brain tissue of Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3), we show that UBQLN2 is selectively recruited to inclusions in HD but not SCA3. Consistent with this result, in a cell-based system mutant HTT interacts with UBQLN2 through the UBA domain while the SCA3 disease protein ATXN3, a deubiquitinating enzyme, does not interact with UBQLN2. Differential recruitment of UBQLN2 to aggregates in HD and SCA3 underscores the heterogeneity of inclusions in polyglutamine diseases and suggests that components of neuronal protein quality control may be differentially perturbed in distinct polyQ diseases.
Perturbations in neuronal protein homeostasis likely contribute to disease pathogenesis in polygl... more Perturbations in neuronal protein homeostasis likely contribute to disease pathogenesis in polyglutamine (polyQ) neurodegenerative disorders. Here we provide evidence that the co-chaperone and ubiquitin ligase, CHIP (C-terminus of Hsp70-interacting protein), is a central component to the homeostatic mechanisms countering toxic polyQ proteins in the brain. Genetic reduction or elimination of CHIP accelerates disease in transgenic mice expressing polyQ-expanded ataxin-3, the disease protein in Spinocerebellar Ataxia Type 3 (SCA3). In parallel, CHIP reduction markedly increases the level of ataxin-3 microaggregates, which partition in the soluble fraction of brain lysates yet are resistant to dissociation with denaturing detergent, and which precede the appearance of inclusions. The level of microaggregates in the CNS, but not of ataxin-3 monomer, correlates with disease severity. Additional cell-based studies suggest that either of two quality control ubiquitin ligases, CHIP or E4B, can reduce steady state levels of expanded, but not wild-type, ataxin-3. Our results support an aggregation model of polyQ disease pathogenesis in which ataxin-3 microaggregates are a neurotoxic species, and suggest that enhancing CHIP activity is a possible route to therapy for SCA3 and other polyQ diseases.
The aggregation of mutant polyglutamine (polyQ) proteins has sparked interest in the role of prot... more The aggregation of mutant polyglutamine (polyQ) proteins has sparked interest in the role of protein qualitycontrol pathways in Huntington's disease (HD) and related polyQ disorders. Employing a novel knock-in HD mouse model, we provide in vivo evidence of early, sustained alterations of autophagy in response to mutant huntingtin (mhtt). The HdhQ200 knock-in model, derived from the selective breeding of HdhQ150 knock-in mice, manifests an accelerated and more robust phenotype than the parent line. Heterozygous HdhQ200 mice accumulate htt aggregates as cytoplasmic aggregation foci (AF) as early as 9 weeks of age and striatal neuronal intranuclear inclusions (NIIs) by 20 weeks. By 40 weeks, striatal AF are perinuclear and immunoreactive for ubiquitin and the autophagosome marker LC3. Striatal NIIs accumulate earlier in HdhQ200 mice than in HdhQ150 mice. The earlier appearance of aggregate pathology in HdhQ200 mice is paralleled by earlier and more rapidly progressive motor deficits: progressive imbalance and decreased motor coordination by 50 weeks, gait deficits by 60 weeks and gross motor impairment by 80 weeks of age. At 80 weeks, heterozygous HdhQ200 mice exhibit striatal and cortical astrogliosis and a ∼50% reduction in striatal dopamine receptor binding. Increased LC3-II protein expression, which is noted early and sustained throughout the disease course, is paralleled by increased expression of the autophagy-related protein, p62. Early and sustained expression of autophagy-related proteins in this genetically precise mouse model of HD suggests that the alteration of autophagic flux is an important and early component of the neuronal response to mhtt.
The functions of the deubiquitinating enzymes JosD1 and JosD2, related to ATXN3, are unknown. Res... more The functions of the deubiquitinating enzymes JosD1 and JosD2, related to ATXN3, are unknown. Results: JosD1 is activated by ubiquitination, localizes to plasma membrane, and affects membrane dynamics, cell motility, and endocytosis. Conclusion: JosD1 and JosD2 possess divergent properties, with JosD1 regulating membrane-related functions. Significance: Our findings provide insight into diverse functions of a disease-linked family of deubiquitinating enzymes. The functional diversity of deubiquitinating enzymes (DUBs) is not well understood. The MJD family of DUBs consists of four cysteine proteases that share a catalytic "Josephin" domain. The family is named after the DUB ATXN3, which causes the neurodegenerative disease Machado-Joseph disease. The two closely related Josephin domain-containing (JosD) proteins 1 and 2 consist of little more than the Josephin domain. To gain insight into the properties of Josephin domains, we investigated JosD1 and JosD2. JosD1 and JosD2 were found to differ fundamentally in many respects. In vitro, only JosD2 can cleave ubiquitin chains. In contrast, JosD1 cleaves ubiquitin chains only after it is monoubiquitinated, a form of posttranslational-dependent regulation shared with ATXN3. A significant fraction of JosD1 is monoubiquitinated in diverse mouse tissues. In cell-based studies, JosD2 localizes to the cytoplasm whereas JosD1 preferentially localizes to the plasma membrane, particularly when ubiquitinated. The membrane occupancy by JosD1 suggests that it could participate in membrane-dependent events such as cell motility and endocytosis. Indeed, time-lapse imaging revealed that JosD1 enhances membrane dynamics and cell motility. JosD1 also influences endocytosis in cultured cells by increasing the uptake of endocytic markers of macropinocytosis while decreasing those for clathrin-and caveolae-mediated endocytosis. Our results establish that two closely related DUBs differ markedly in activity and function and that JosD1, a membrane-associated DUB whose activity is regulated by ubiquitination, helps regulate membrane dynamics, cell motility, and endocytosis.
Polyglutamine diseases are a major cause of neurodegenerative disease worldwide. Recent studies h... more Polyglutamine diseases are a major cause of neurodegenerative disease worldwide. Recent studies highlight the importance of protein quality control mechanisms in regulating polyglutamine-induced toxicity. Drawing on these studies, we propose a model of disease pathogenesis that integrates current understanding of the role of protein folding in polyglutamine disease. We also incorporate new findings on other age-related neurodegenerative diseases in an effort to explain how protein aggregation and normal aging processes might be involved in polyglutamine disease pathogenesis.
Ataxin-3 is a deubiquitinating enzyme (DUB) that participates in ubiquitin-dependent protein qual... more Ataxin-3 is a deubiquitinating enzyme (DUB) that participates in ubiquitin-dependent protein quality control pathways and, based on studies in model systems, may be neuroprotective against toxic polyglutamine proteins such as the Huntington's disease (HD) protein, huntingtin (htt). HD is one of at least nine polyglutamine neurodegenerative diseases in which disease-causing proteins accumulate in ubiquitin-positive inclusions within neurons. In studies crossing mice null for ataxin-3 to an established HD knock-in mouse model (HdhQ200), we tested whether loss of ataxin-3 alters disease progression, perhaps by impairing the clearance of mutant htt or the ubiquitination of inclusions. While loss of ataxin-3 mildly exacerbated age-dependent motor deficits, it did not alter inclusion formation, ubiquitination of inclusions or levels of mutant or normal htt. Ataxin-3, itself a polyglutamine-containing protein with multiple ubiquitin binding domains, was not observed to localize to htt inclusions. Changes in neurotransmitter receptor binding known to occur in HD knock-in mice also were not altered by the loss of ataxin-3, although we unexpectedly observed increased GABA A receptor binding in the striatum of HdhQ200 mice, which has not previously been noted. Finally, we confirmed that CNS levels of hsp70 are decreased in HD mice as has been reported in other HD mouse models, regardless of the presence or absence of ataxin-3. We conclude that while ataxin-3 may participate in protein quality control pathways, it does not critically regulate the handling of mutant htt or contribute to major features of disease pathogenesis in HD.
Many pathways important to the nervous system are regulated by the post-translational conjugation... more Many pathways important to the nervous system are regulated by the post-translational conjugation of ubiquitin to target proteins. The reversal of ubiquitination, or deubiquitination, is equally critical to neuronal function. By countering protein ubiquitination, deubiquitinating enzymes (DUBs) help control neuronal fate determination, axonal pathfinding, and synaptic communication and plasticity. The significance of DUBs to the nervous system is underscored by links to various neurological diseases. Due to cell type or substrate specificity, certain DUBs may also represent therapeutic targets for neurodegeneration. Here, we review recent findings which have shaped our current understanding of emerging functions for DUB in the nervous system. The development and function of the nervous system depends on cellular processes ranging from DNA transcription to protein degradation and on conserved signaling pathways between and within cells. These diverse processes and pathways rely on key regulatory elements that dictate the "when" and the "how" of neuronal development, function and disease. One such element is the post-translational conjugation of ubiquitin (Ub; Glossary) to proteins. An evolutionarily conserved 8.5 kDa protein expressed in all eukaryotic cells, Ub modulates the function of target proteins to which it is conjugated. Ub first captured the interest of neuroscientists due to its presence in proteinaceous accumulations in various neurodegenerative diseases including, neurofibrillary tangles in Alzheimer's Disease (AD), Lewy Bodies in Parkinson's Disease (PD), and intranuclear inclusions in hereditary polyglutamine disorders . Conjugation of Ub to proteins, or ubiquitination, occurs through the action of three classes of enzymes: E1 (Ub Activating Enzyme), E2 (Ub Conjugating Enzyme) and E3 (Ub Ligase; see Box 1). Because Ub molecules can be attached to other Ubs through any one of 7 lysines to form chains, a target protein can be modified by a single Ub (mono-ubiquitination) or by a poly-Ub chain. Depending on the type of ubiquitination (i.e. mono-or poly-Ub, and/or the type of Ub-Ub linkages), the conjugated protein is subjected to different fates (Box 1). Ub-Ub linkages through lysine 48 ("K48") generally target proteins for degradation, while Ub-Ub linkages
1Spinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease, is the most common d... more 1Spinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease, is the most common dominantly inherited ataxia. SCA3 is caused by a CAG repeat expansion in theATXN3gene that encodes an expanded tract of polyglutamine (polyQ) in the disease protein ataxin-3 (ATXN3). As a deubiquitinating enzyme, ATXN3 regulates numerous cellular processes including proteasome- and autophagy-mediated protein degradation. In SCA3 disease brain, polyQ-expanded ATXN3 accumulates with other cellular constituents, including ubiquitin (Ub)-modified proteins, in select areas like the cerebellum and the brainstem, but whether pathogenic ATXN3 affects the abundance of ubiquitinated species is unknown. Here, in mouse and cellular models of SCA3, we investigated whether elimination of murineAtxn3or expression of wild-type or polyQ-expanded human ATXN3 alters soluble levels of overall ubiquitination, as well as K48-linked (K48-Ub) and K63-linked (K63-Ub) chains. Levels of ubiquitination were assessed...
The brain expressed ubiquilins (UBQLNs) 1, 2 and 4 are a family of ubiquitin adaptor proteins tha... more The brain expressed ubiquilins (UBQLNs) 1, 2 and 4 are a family of ubiquitin adaptor proteins that participate broadly in protein quality control (PQC) pathways, including the ubiquitin proteasome system (UPS). One family member, UBQLN2, has been implicated in numerous neurodegenerative diseases including ALS/FTD. UBQLN2 typically resides in the cytoplasm but in disease can translocate to the nucleus, as in Huntington’s disease where it promotes the clearance of mutant Huntingtin protein. How UBQLN2 translocates to the nucleus and clears aberrant nuclear proteins, however, is not well understood. In a mass spectrometry screen to discover UBQLN2 interactors, we identified a family of small (13 kDa), highly homologous uncharacterized proteins, RTL8, and confirmed the interaction between UBQLN2 and RTL8 both in vitro using recombinant proteins and in vivo using mouse brain tissue. Under endogenous and overexpressed conditions, RTL8 localizes to nucleoli. When co-expressed with UBQLN2, ...
The interplay between NOD2 and TLR2 following recognition of components of the bacterial cell wal... more The interplay between NOD2 and TLR2 following recognition of components of the bacterial cell wall peptidoglycan is well established, however their role in redirecting metabolic pathways in myeloid cells to degrade pathogens and mount antigen presentation remains unclear. We show NOD2 and TLR2 mediate phosphorylation of the deubiquitinase ataxin-3 via RIPK2 and TBK1. In myeloid cells ataxin-3 associates with the mitochondrial cristae protein MIC60, and is required for oxidative phosphorylation. Depletion of ataxin-3 leads to impaired induction of mitochondrial reactive oxygen species (mROS) and defective bacterial killing. A mass spectrometry analysis of NOD2/TLR2 triggered ataxin-3 deubiquitination targets revealed immunometabolic regulators, including HIF-1α and LAMTOR1 that may contribute to these effects. Thus, we define how ataxin-3 plays an essential role in NOD2 and TLR2 sensing and effector functions in myeloid cells.Significance StatementIn recent years it has become clear ...
Background: Cerebellar degenerative pathology has been identified in tremor patients; however, ho... more Background: Cerebellar degenerative pathology has been identified in tremor patients; however, how the degenerative pathology could contribute to tremor remains unclear. If the cerebellar degenerative pathology can directly drive tremor, one would hypothesize that tremor is likely to occur in the diseases of cerebellar ataxia and follows the disease progression in such disorders. To further test this hypothesis, we studied the occurrence of tremor in different disease stages of classical cerebellar degenerative disorders: spinocerebellar ataxias (SCAs). We further separately analyzed postural tremor and rest tremor, two forms of tremor that both involve the cerebellum. We also explored tremor in different subtypes of SCAs. We found that 18.1% of SCA patients have tremor. Interestingly, SCA patients with tremor have worse ataxia than those without tremor. When stratifying patients into mild, moderate, and severe disease stages according to the severity of ataxia, moderate and severe SCA patients more commonly have tremor than those with mild ataxia, the effect most prominently observed in postural tremor of SCA3 and SCA6 patients. Finally, tremor can independently contribute to worse functional status in SCA2 patients, even after adjusting for ataxia severity. Tremor is more likely to occur in the severe stage of cerebellar degeneration when compared to mild stages. Our results partially support the cerebellar degenerative model of tremor.
Tremor and other hyperkinetic movements (New York, N.Y.), 2017
Postural tremor can sometimes occur in spinocerebellar ataxias (SCAs). However, the prevalence an... more Postural tremor can sometimes occur in spinocerebellar ataxias (SCAs). However, the prevalence and clinical characteristics of postural tremor in SCAs are poorly understood, and whether SCA patients with postural tremor have different ataxia progression is not known. We studied postural tremor in 315 patients with SCA1, 2, 3, and 6 recruited from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA), which consists of 12 participating centers in the United States, and we evaluated ataxia progression in these patients from January 2010 to August 2012. Among 315 SCA patients, postural tremor was most common in SCA2 patients (SCA1, 5.8%; SCA2, 27.5%; SCA3, 12.4%; SCA6, 16.9%; p = 0.007). SCA3 patients with postural tremor had longer CAG repeat expansions than SCA3 patients without postural tremor (73.67 ± 3.12 vs. 70.42 ± 3.96, p = 0.003). Interestingly, SCA1 and SCA6 patients with postural tremor had a slower rate of ataxia progression (SCA1, β = -0.91, p < 0.001; ...
Dystonia is a common feature in spinocerebellar ataxias (SCAs). Whether the presence of dystonia ... more Dystonia is a common feature in spinocerebellar ataxias (SCAs). Whether the presence of dystonia is associated with different rate of ataxia progression is not known. To study clinical characteristics and ataxia progression in SCAs with and without dystonia. We studied 334 participants with SCA 1, 2, 3 and 6 from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) and compared the clinical characteristics of SCAs with and without dystonia. We repeatedly measured ataxia progression by the Scale for Assessment and Rating of Ataxia every 6 months for 2 years. Regression models were employed to study the association between dystonia and ataxia progression after adjusting for age, sex and pathological CAG repeats. We used logistic regression to analyze the impact of different repeat expansion genes on dystonia in SCAs. Dystonia was most commonly observed in SCA3, followed by SCA2, SCA1, and SCA6. Dystonia was associated with longer CAG repeats in SCA3. The CAG repeat n...
Background-Depression is a common comorbidity in spinocerebellar ataxias (SCAs) but its associati... more Background-Depression is a common comorbidity in spinocerebellar ataxias (SCAs) but its association with ataxia progression is not well understood. Objectives-To study the prevalence and influence of depressive symptoms in SCAs. Methods-We studied 300 participants with SCA 1, 2, 3 and 6 from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) and repeatedly measured depressive symptoms by the 9-item Patient Health Questionnaire (PHQ-9) along with other clinical features including ataxia, functional status, and quality of life every 6 months for 2 years. We employed regression models to study the effects of depressive symptoms on clinical progression indexed by Scale for Assessment and Rating of Ataxia (SARA), Unified Huntington's Disease Rating Scale Part IV (UHDRS-IV) and EQ5D after adjusting for age, sex and pathological CAG repeats. Results-Comorbid depression is common in SCAs (26%). Although the baseline prevalence of depression was similar among different SCA types, suicidal ideation was more frequently reported in SCA3 (65%). Depressive symptoms were associated with SARA scores but did not significantly progress over time within 2 years or deteriorate by increased numbers of pathological CAG repeats. The effects of depression on ataxia progression varied across different SCA types. Nevertheless, depression had consistently negative and significant impact on functional status and quality of life in all SCAs, even after accounting for ataxia progression. Conclusions-Depressive symptoms are not simply the consequence of motor disability in SCAs. Comorbid depression per se contributes to different health outcomes and deserves more attention when caring patients with SCAs.
Fragile X-associated Tremor Ataxia Syndrome (FXTAS) is a neurodegenerative disorder caused by a C... more Fragile X-associated Tremor Ataxia Syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG trinucleotide repeat expansion in the 5'UTR of the Fragile X gene, FMR1. FXTAS is thought to arise primarily from an RNA gain-of-function toxicity mechanism. However, recent studies demonstrate that the repeat also elicits production of a toxic polyglycine protein, FMRpolyG, via Repeat-Associated Non-AUG (RAN) initiated translation. Pathologically, FXTAS is characterized by ubiquitin positive intranuclear neuronal inclusions, raising the possibility that failure of protein quality control pathways could contribute to disease pathogenesis. To test this hypothesis, we used Drosophila and cell based models of CGG-repeat associated toxicity. In Drosophila, ubiquitin proteasome system (UPS) impairment led to enhancement of CGG-repeat induced degeneration whereas overexpression of the chaperone protein HSP70 suppressed this toxicity. In transfected mammalian cells, CGG-repeat expression...
Ataxin-3, the protein responsible for spinocerebellar ataxia type-3, is a cysteine protease that ... more Ataxin-3, the protein responsible for spinocerebellar ataxia type-3, is a cysteine protease that specifically cleaves poly-ubiquitin chains and participates in the ubiquitin proteasome pathway. The enzymatic activity resides in the N-terminal Josephin domain. An unusual feature of ataxin-3 is its low enzymatic activity especially for mono-ubiquitinated substrates and short ubiquitin chains. However, specific ubiquitination at lysine 117 in the Josephin domain activates ataxin-3 through an unknown mechanism. Here, we investigate the effects of K117 ubiquitination on the structure and enzymatic activity of the protein. We show that covalently linked ubiquitin rests on the Josephin domain, forming a compact globular moiety and occupying a ubiquitin binding site previously thought to be essential for substrate recognition. In doing so, ubiquitination enhances enzymatic activity by locking the enzyme in an activated state. Our results indicate that ubiquitin functions both as a substrate and as an allosteric regulatory factor. We provide a novel example in which a conformational switch controls the activity of an enzyme that mediates deubiquitination.
Genetic factors are now recognized to play an important role in most age-related dementias. While... more Genetic factors are now recognized to play an important role in most age-related dementias. While other factors, including aging itself, contribute to dementia, in this review we focus on the role of specific disease-causing genes and genetic factors in the most common age-related dementias. We review each dementia within the context of a genes/environment continuum, with varying levels of genetic versus environmental influence. All major classes of dementia will be discussed but greatest attention will be given to the most common dementia, Alzheimer's disease, for which several new genetic factors were recently identified.
The past 25 years have seen enormous progress in the deciphering of the genetic and molecular bas... more The past 25 years have seen enormous progress in the deciphering of the genetic and molecular basis of ataxias, resulting in improved understanding of their pathogenesis. The most significant milestones during this period were the cloning of the genes associated with the common spinocerebellar ataxias, ataxia telangiectasia, and Friedreich ataxia. To date, the causative mutations of more than 30 spinocerebellar ataxias and 20 recessive ataxias have been identified. In addition, there are numerous acquired ataxias with defined molecular causes, so that the entire number of distinct ataxia disorders exceeds 50 and possibly approaches 100. Despite this enormous heterogeneity, a few recurrent pathophysiological themes stand out. These include protein aggregation, failure of protein homeostasis, perturbations in ion channel function, defects in DNA repair, and mitochondrial dysfunction. The clinical phenotypes of the most common ataxia disorders have been firmly established, and their natural history is being studied in ongoing large observational trials. Effective therapies for ataxias are still lacking. However, novel drug targets are under investigation, and it is expected that there will be an increasing number of therapeutic trials in ataxia. V
The spinocerebellar ataxias (SCAs) comprise more than 40 autosomal dominant neurodegenerative dis... more The spinocerebellar ataxias (SCAs) comprise more than 40 autosomal dominant neurodegenerative disorders that present principally with progressive ataxia. Within the past few years, studies of pathogenic mechanisms in the SCAs have led to the development of promising therapeutic strategies, especially for SCAs caused by polyglutamine-coding CAG repeats. Nucleotide-based gene-silencing approaches that target the first steps in the pathogenic cascade are one promising approach not only for polyglutamine SCAs but also for the many other SCAs caused by toxic mutant proteins or RNA. For these and other emerging therapeutic strategies, wellcoordinated preparation is needed for fruitful clinical trials. To accomplish this goal, investigators from the United States and Europe are now collaborating to share data from their respective SCA cohorts. Increased knowledge of the natural history of SCAs, including of the premanifest and early symptomatic stages of disease, will improve the prospects for success in clinical trials of disease-modifying drugs. In addition, investigators are seeking validated clinical outcome measures that demonstrate responsiveness to changes in SCA populations. Findings suggest that MRI and magnetic resonance spectroscopy biomarkers will provide objective biological readouts of disease activity and progression, but more work is needed to establish disease-specific biomarkers that track target engagement in therapeutic trials. Together, these efforts suggest that the development of successful therapies for one or more SCAs is not far away. The spinocerebellar ataxias (SCAs) are a group of autosomal dominant disorders characterized by progressive ataxia due to degeneration of the cerebellum and its afferent and efferent pathways 1 . The prefix 'SCA' with an associated number (which reflects the order of genetic discovery) is assigned to dominantly inherited ataxias when their genetic loci are defined. Although the term SCA describes a broad category of disorders in which *
Huntington's Disease (HD) is caused by a CAG repeat expansion that encodes a polyglutamine (polyQ... more Huntington's Disease (HD) is caused by a CAG repeat expansion that encodes a polyglutamine (polyQ) expansion in the HD disease protein, huntingtin (HTT). PolyQ expansion promotes misfolding and aggregation of mutant HTT (mHTT) within neurons. The cellular pathways, including ubiquitin-dependent processes, by which mHTT is regulated remain incompletely understood. Ube2W is the only ubiquitin conjugating enzyme (E2) known to ubiquitinate substrates at their amino (N)-termini, likely favoring substrates with disordered N-termini. By virtue of its N-terminal polyQ domain, HTT has an intrinsically disordered amino terminus. In studies employing immortalized cells, primary neurons and a knock-in (KI) mouse model of HD, we tested the effect of Ube2W deficiency on mHTT levels, aggregation and neurotoxicity. In cultured cells, deficiency of Ube2W activity markedly decreases mHTT aggregate formation and increases the level of soluble monomers, while reducing mHTT-induced cytotoxicity. Consistent with this result, the absence of Ube2W in HdhQ200 KI mice significantly increases levels of soluble monomeric mHTT while reducing insoluble oligomeric species. This study sheds light on the potential function of the non-canonical ubiquitin-conjugating enzyme, Ube2W, in this polyQ neurodegenerative disease.
Accumulation of mutant polyglutamine proteins in intraneuronal inclusions is a hallmark of polygl... more Accumulation of mutant polyglutamine proteins in intraneuronal inclusions is a hallmark of polyglutamine diseases. Impairment of protein clearance systems and sequestration of clearancerelated proteins into inclusions occur in many protein folding diseases, including the polyglutamine diseases. The ubiquitin-binding and proteasome adaptor protein UBQLN2 participates in protein homeostasis and localizes to inclusions in various neurodegenerative diseases. Employing mouse models and human brain tissue of Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3), we show that UBQLN2 is selectively recruited to inclusions in HD but not SCA3. Consistent with this result, in a cell-based system mutant HTT interacts with UBQLN2 through the UBA domain while the SCA3 disease protein ATXN3, a deubiquitinating enzyme, does not interact with UBQLN2. Differential recruitment of UBQLN2 to aggregates in HD and SCA3 underscores the heterogeneity of inclusions in polyglutamine diseases and suggests that components of neuronal protein quality control may be differentially perturbed in distinct polyQ diseases.
Perturbations in neuronal protein homeostasis likely contribute to disease pathogenesis in polygl... more Perturbations in neuronal protein homeostasis likely contribute to disease pathogenesis in polyglutamine (polyQ) neurodegenerative disorders. Here we provide evidence that the co-chaperone and ubiquitin ligase, CHIP (C-terminus of Hsp70-interacting protein), is a central component to the homeostatic mechanisms countering toxic polyQ proteins in the brain. Genetic reduction or elimination of CHIP accelerates disease in transgenic mice expressing polyQ-expanded ataxin-3, the disease protein in Spinocerebellar Ataxia Type 3 (SCA3). In parallel, CHIP reduction markedly increases the level of ataxin-3 microaggregates, which partition in the soluble fraction of brain lysates yet are resistant to dissociation with denaturing detergent, and which precede the appearance of inclusions. The level of microaggregates in the CNS, but not of ataxin-3 monomer, correlates with disease severity. Additional cell-based studies suggest that either of two quality control ubiquitin ligases, CHIP or E4B, can reduce steady state levels of expanded, but not wild-type, ataxin-3. Our results support an aggregation model of polyQ disease pathogenesis in which ataxin-3 microaggregates are a neurotoxic species, and suggest that enhancing CHIP activity is a possible route to therapy for SCA3 and other polyQ diseases.
The aggregation of mutant polyglutamine (polyQ) proteins has sparked interest in the role of prot... more The aggregation of mutant polyglutamine (polyQ) proteins has sparked interest in the role of protein qualitycontrol pathways in Huntington's disease (HD) and related polyQ disorders. Employing a novel knock-in HD mouse model, we provide in vivo evidence of early, sustained alterations of autophagy in response to mutant huntingtin (mhtt). The HdhQ200 knock-in model, derived from the selective breeding of HdhQ150 knock-in mice, manifests an accelerated and more robust phenotype than the parent line. Heterozygous HdhQ200 mice accumulate htt aggregates as cytoplasmic aggregation foci (AF) as early as 9 weeks of age and striatal neuronal intranuclear inclusions (NIIs) by 20 weeks. By 40 weeks, striatal AF are perinuclear and immunoreactive for ubiquitin and the autophagosome marker LC3. Striatal NIIs accumulate earlier in HdhQ200 mice than in HdhQ150 mice. The earlier appearance of aggregate pathology in HdhQ200 mice is paralleled by earlier and more rapidly progressive motor deficits: progressive imbalance and decreased motor coordination by 50 weeks, gait deficits by 60 weeks and gross motor impairment by 80 weeks of age. At 80 weeks, heterozygous HdhQ200 mice exhibit striatal and cortical astrogliosis and a ∼50% reduction in striatal dopamine receptor binding. Increased LC3-II protein expression, which is noted early and sustained throughout the disease course, is paralleled by increased expression of the autophagy-related protein, p62. Early and sustained expression of autophagy-related proteins in this genetically precise mouse model of HD suggests that the alteration of autophagic flux is an important and early component of the neuronal response to mhtt.
The functions of the deubiquitinating enzymes JosD1 and JosD2, related to ATXN3, are unknown. Res... more The functions of the deubiquitinating enzymes JosD1 and JosD2, related to ATXN3, are unknown. Results: JosD1 is activated by ubiquitination, localizes to plasma membrane, and affects membrane dynamics, cell motility, and endocytosis. Conclusion: JosD1 and JosD2 possess divergent properties, with JosD1 regulating membrane-related functions. Significance: Our findings provide insight into diverse functions of a disease-linked family of deubiquitinating enzymes. The functional diversity of deubiquitinating enzymes (DUBs) is not well understood. The MJD family of DUBs consists of four cysteine proteases that share a catalytic "Josephin" domain. The family is named after the DUB ATXN3, which causes the neurodegenerative disease Machado-Joseph disease. The two closely related Josephin domain-containing (JosD) proteins 1 and 2 consist of little more than the Josephin domain. To gain insight into the properties of Josephin domains, we investigated JosD1 and JosD2. JosD1 and JosD2 were found to differ fundamentally in many respects. In vitro, only JosD2 can cleave ubiquitin chains. In contrast, JosD1 cleaves ubiquitin chains only after it is monoubiquitinated, a form of posttranslational-dependent regulation shared with ATXN3. A significant fraction of JosD1 is monoubiquitinated in diverse mouse tissues. In cell-based studies, JosD2 localizes to the cytoplasm whereas JosD1 preferentially localizes to the plasma membrane, particularly when ubiquitinated. The membrane occupancy by JosD1 suggests that it could participate in membrane-dependent events such as cell motility and endocytosis. Indeed, time-lapse imaging revealed that JosD1 enhances membrane dynamics and cell motility. JosD1 also influences endocytosis in cultured cells by increasing the uptake of endocytic markers of macropinocytosis while decreasing those for clathrin-and caveolae-mediated endocytosis. Our results establish that two closely related DUBs differ markedly in activity and function and that JosD1, a membrane-associated DUB whose activity is regulated by ubiquitination, helps regulate membrane dynamics, cell motility, and endocytosis.
Polyglutamine diseases are a major cause of neurodegenerative disease worldwide. Recent studies h... more Polyglutamine diseases are a major cause of neurodegenerative disease worldwide. Recent studies highlight the importance of protein quality control mechanisms in regulating polyglutamine-induced toxicity. Drawing on these studies, we propose a model of disease pathogenesis that integrates current understanding of the role of protein folding in polyglutamine disease. We also incorporate new findings on other age-related neurodegenerative diseases in an effort to explain how protein aggregation and normal aging processes might be involved in polyglutamine disease pathogenesis.
Ataxin-3 is a deubiquitinating enzyme (DUB) that participates in ubiquitin-dependent protein qual... more Ataxin-3 is a deubiquitinating enzyme (DUB) that participates in ubiquitin-dependent protein quality control pathways and, based on studies in model systems, may be neuroprotective against toxic polyglutamine proteins such as the Huntington's disease (HD) protein, huntingtin (htt). HD is one of at least nine polyglutamine neurodegenerative diseases in which disease-causing proteins accumulate in ubiquitin-positive inclusions within neurons. In studies crossing mice null for ataxin-3 to an established HD knock-in mouse model (HdhQ200), we tested whether loss of ataxin-3 alters disease progression, perhaps by impairing the clearance of mutant htt or the ubiquitination of inclusions. While loss of ataxin-3 mildly exacerbated age-dependent motor deficits, it did not alter inclusion formation, ubiquitination of inclusions or levels of mutant or normal htt. Ataxin-3, itself a polyglutamine-containing protein with multiple ubiquitin binding domains, was not observed to localize to htt inclusions. Changes in neurotransmitter receptor binding known to occur in HD knock-in mice also were not altered by the loss of ataxin-3, although we unexpectedly observed increased GABA A receptor binding in the striatum of HdhQ200 mice, which has not previously been noted. Finally, we confirmed that CNS levels of hsp70 are decreased in HD mice as has been reported in other HD mouse models, regardless of the presence or absence of ataxin-3. We conclude that while ataxin-3 may participate in protein quality control pathways, it does not critically regulate the handling of mutant htt or contribute to major features of disease pathogenesis in HD.
Many pathways important to the nervous system are regulated by the post-translational conjugation... more Many pathways important to the nervous system are regulated by the post-translational conjugation of ubiquitin to target proteins. The reversal of ubiquitination, or deubiquitination, is equally critical to neuronal function. By countering protein ubiquitination, deubiquitinating enzymes (DUBs) help control neuronal fate determination, axonal pathfinding, and synaptic communication and plasticity. The significance of DUBs to the nervous system is underscored by links to various neurological diseases. Due to cell type or substrate specificity, certain DUBs may also represent therapeutic targets for neurodegeneration. Here, we review recent findings which have shaped our current understanding of emerging functions for DUB in the nervous system. The development and function of the nervous system depends on cellular processes ranging from DNA transcription to protein degradation and on conserved signaling pathways between and within cells. These diverse processes and pathways rely on key regulatory elements that dictate the "when" and the "how" of neuronal development, function and disease. One such element is the post-translational conjugation of ubiquitin (Ub; Glossary) to proteins. An evolutionarily conserved 8.5 kDa protein expressed in all eukaryotic cells, Ub modulates the function of target proteins to which it is conjugated. Ub first captured the interest of neuroscientists due to its presence in proteinaceous accumulations in various neurodegenerative diseases including, neurofibrillary tangles in Alzheimer's Disease (AD), Lewy Bodies in Parkinson's Disease (PD), and intranuclear inclusions in hereditary polyglutamine disorders . Conjugation of Ub to proteins, or ubiquitination, occurs through the action of three classes of enzymes: E1 (Ub Activating Enzyme), E2 (Ub Conjugating Enzyme) and E3 (Ub Ligase; see Box 1). Because Ub molecules can be attached to other Ubs through any one of 7 lysines to form chains, a target protein can be modified by a single Ub (mono-ubiquitination) or by a poly-Ub chain. Depending on the type of ubiquitination (i.e. mono-or poly-Ub, and/or the type of Ub-Ub linkages), the conjugated protein is subjected to different fates (Box 1). Ub-Ub linkages through lysine 48 ("K48") generally target proteins for degradation, while Ub-Ub linkages
1Spinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease, is the most common d... more 1Spinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease, is the most common dominantly inherited ataxia. SCA3 is caused by a CAG repeat expansion in theATXN3gene that encodes an expanded tract of polyglutamine (polyQ) in the disease protein ataxin-3 (ATXN3). As a deubiquitinating enzyme, ATXN3 regulates numerous cellular processes including proteasome- and autophagy-mediated protein degradation. In SCA3 disease brain, polyQ-expanded ATXN3 accumulates with other cellular constituents, including ubiquitin (Ub)-modified proteins, in select areas like the cerebellum and the brainstem, but whether pathogenic ATXN3 affects the abundance of ubiquitinated species is unknown. Here, in mouse and cellular models of SCA3, we investigated whether elimination of murineAtxn3or expression of wild-type or polyQ-expanded human ATXN3 alters soluble levels of overall ubiquitination, as well as K48-linked (K48-Ub) and K63-linked (K63-Ub) chains. Levels of ubiquitination were assessed...
The brain expressed ubiquilins (UBQLNs) 1, 2 and 4 are a family of ubiquitin adaptor proteins tha... more The brain expressed ubiquilins (UBQLNs) 1, 2 and 4 are a family of ubiquitin adaptor proteins that participate broadly in protein quality control (PQC) pathways, including the ubiquitin proteasome system (UPS). One family member, UBQLN2, has been implicated in numerous neurodegenerative diseases including ALS/FTD. UBQLN2 typically resides in the cytoplasm but in disease can translocate to the nucleus, as in Huntington’s disease where it promotes the clearance of mutant Huntingtin protein. How UBQLN2 translocates to the nucleus and clears aberrant nuclear proteins, however, is not well understood. In a mass spectrometry screen to discover UBQLN2 interactors, we identified a family of small (13 kDa), highly homologous uncharacterized proteins, RTL8, and confirmed the interaction between UBQLN2 and RTL8 both in vitro using recombinant proteins and in vivo using mouse brain tissue. Under endogenous and overexpressed conditions, RTL8 localizes to nucleoli. When co-expressed with UBQLN2, ...
The interplay between NOD2 and TLR2 following recognition of components of the bacterial cell wal... more The interplay between NOD2 and TLR2 following recognition of components of the bacterial cell wall peptidoglycan is well established, however their role in redirecting metabolic pathways in myeloid cells to degrade pathogens and mount antigen presentation remains unclear. We show NOD2 and TLR2 mediate phosphorylation of the deubiquitinase ataxin-3 via RIPK2 and TBK1. In myeloid cells ataxin-3 associates with the mitochondrial cristae protein MIC60, and is required for oxidative phosphorylation. Depletion of ataxin-3 leads to impaired induction of mitochondrial reactive oxygen species (mROS) and defective bacterial killing. A mass spectrometry analysis of NOD2/TLR2 triggered ataxin-3 deubiquitination targets revealed immunometabolic regulators, including HIF-1α and LAMTOR1 that may contribute to these effects. Thus, we define how ataxin-3 plays an essential role in NOD2 and TLR2 sensing and effector functions in myeloid cells.Significance StatementIn recent years it has become clear ...
Background: Cerebellar degenerative pathology has been identified in tremor patients; however, ho... more Background: Cerebellar degenerative pathology has been identified in tremor patients; however, how the degenerative pathology could contribute to tremor remains unclear. If the cerebellar degenerative pathology can directly drive tremor, one would hypothesize that tremor is likely to occur in the diseases of cerebellar ataxia and follows the disease progression in such disorders. To further test this hypothesis, we studied the occurrence of tremor in different disease stages of classical cerebellar degenerative disorders: spinocerebellar ataxias (SCAs). We further separately analyzed postural tremor and rest tremor, two forms of tremor that both involve the cerebellum. We also explored tremor in different subtypes of SCAs. We found that 18.1% of SCA patients have tremor. Interestingly, SCA patients with tremor have worse ataxia than those without tremor. When stratifying patients into mild, moderate, and severe disease stages according to the severity of ataxia, moderate and severe SCA patients more commonly have tremor than those with mild ataxia, the effect most prominently observed in postural tremor of SCA3 and SCA6 patients. Finally, tremor can independently contribute to worse functional status in SCA2 patients, even after adjusting for ataxia severity. Tremor is more likely to occur in the severe stage of cerebellar degeneration when compared to mild stages. Our results partially support the cerebellar degenerative model of tremor.
Tremor and other hyperkinetic movements (New York, N.Y.), 2017
Postural tremor can sometimes occur in spinocerebellar ataxias (SCAs). However, the prevalence an... more Postural tremor can sometimes occur in spinocerebellar ataxias (SCAs). However, the prevalence and clinical characteristics of postural tremor in SCAs are poorly understood, and whether SCA patients with postural tremor have different ataxia progression is not known. We studied postural tremor in 315 patients with SCA1, 2, 3, and 6 recruited from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA), which consists of 12 participating centers in the United States, and we evaluated ataxia progression in these patients from January 2010 to August 2012. Among 315 SCA patients, postural tremor was most common in SCA2 patients (SCA1, 5.8%; SCA2, 27.5%; SCA3, 12.4%; SCA6, 16.9%; p = 0.007). SCA3 patients with postural tremor had longer CAG repeat expansions than SCA3 patients without postural tremor (73.67 ± 3.12 vs. 70.42 ± 3.96, p = 0.003). Interestingly, SCA1 and SCA6 patients with postural tremor had a slower rate of ataxia progression (SCA1, β = -0.91, p < 0.001; ...
Dystonia is a common feature in spinocerebellar ataxias (SCAs). Whether the presence of dystonia ... more Dystonia is a common feature in spinocerebellar ataxias (SCAs). Whether the presence of dystonia is associated with different rate of ataxia progression is not known. To study clinical characteristics and ataxia progression in SCAs with and without dystonia. We studied 334 participants with SCA 1, 2, 3 and 6 from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) and compared the clinical characteristics of SCAs with and without dystonia. We repeatedly measured ataxia progression by the Scale for Assessment and Rating of Ataxia every 6 months for 2 years. Regression models were employed to study the association between dystonia and ataxia progression after adjusting for age, sex and pathological CAG repeats. We used logistic regression to analyze the impact of different repeat expansion genes on dystonia in SCAs. Dystonia was most commonly observed in SCA3, followed by SCA2, SCA1, and SCA6. Dystonia was associated with longer CAG repeats in SCA3. The CAG repeat n...
Background-Depression is a common comorbidity in spinocerebellar ataxias (SCAs) but its associati... more Background-Depression is a common comorbidity in spinocerebellar ataxias (SCAs) but its association with ataxia progression is not well understood. Objectives-To study the prevalence and influence of depressive symptoms in SCAs. Methods-We studied 300 participants with SCA 1, 2, 3 and 6 from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) and repeatedly measured depressive symptoms by the 9-item Patient Health Questionnaire (PHQ-9) along with other clinical features including ataxia, functional status, and quality of life every 6 months for 2 years. We employed regression models to study the effects of depressive symptoms on clinical progression indexed by Scale for Assessment and Rating of Ataxia (SARA), Unified Huntington's Disease Rating Scale Part IV (UHDRS-IV) and EQ5D after adjusting for age, sex and pathological CAG repeats. Results-Comorbid depression is common in SCAs (26%). Although the baseline prevalence of depression was similar among different SCA types, suicidal ideation was more frequently reported in SCA3 (65%). Depressive symptoms were associated with SARA scores but did not significantly progress over time within 2 years or deteriorate by increased numbers of pathological CAG repeats. The effects of depression on ataxia progression varied across different SCA types. Nevertheless, depression had consistently negative and significant impact on functional status and quality of life in all SCAs, even after accounting for ataxia progression. Conclusions-Depressive symptoms are not simply the consequence of motor disability in SCAs. Comorbid depression per se contributes to different health outcomes and deserves more attention when caring patients with SCAs.
Fragile X-associated Tremor Ataxia Syndrome (FXTAS) is a neurodegenerative disorder caused by a C... more Fragile X-associated Tremor Ataxia Syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG trinucleotide repeat expansion in the 5'UTR of the Fragile X gene, FMR1. FXTAS is thought to arise primarily from an RNA gain-of-function toxicity mechanism. However, recent studies demonstrate that the repeat also elicits production of a toxic polyglycine protein, FMRpolyG, via Repeat-Associated Non-AUG (RAN) initiated translation. Pathologically, FXTAS is characterized by ubiquitin positive intranuclear neuronal inclusions, raising the possibility that failure of protein quality control pathways could contribute to disease pathogenesis. To test this hypothesis, we used Drosophila and cell based models of CGG-repeat associated toxicity. In Drosophila, ubiquitin proteasome system (UPS) impairment led to enhancement of CGG-repeat induced degeneration whereas overexpression of the chaperone protein HSP70 suppressed this toxicity. In transfected mammalian cells, CGG-repeat expression...
Ataxin-3, the protein responsible for spinocerebellar ataxia type-3, is a cysteine protease that ... more Ataxin-3, the protein responsible for spinocerebellar ataxia type-3, is a cysteine protease that specifically cleaves poly-ubiquitin chains and participates in the ubiquitin proteasome pathway. The enzymatic activity resides in the N-terminal Josephin domain. An unusual feature of ataxin-3 is its low enzymatic activity especially for mono-ubiquitinated substrates and short ubiquitin chains. However, specific ubiquitination at lysine 117 in the Josephin domain activates ataxin-3 through an unknown mechanism. Here, we investigate the effects of K117 ubiquitination on the structure and enzymatic activity of the protein. We show that covalently linked ubiquitin rests on the Josephin domain, forming a compact globular moiety and occupying a ubiquitin binding site previously thought to be essential for substrate recognition. In doing so, ubiquitination enhances enzymatic activity by locking the enzyme in an activated state. Our results indicate that ubiquitin functions both as a substrate and as an allosteric regulatory factor. We provide a novel example in which a conformational switch controls the activity of an enzyme that mediates deubiquitination.
Genetic factors are now recognized to play an important role in most age-related dementias. While... more Genetic factors are now recognized to play an important role in most age-related dementias. While other factors, including aging itself, contribute to dementia, in this review we focus on the role of specific disease-causing genes and genetic factors in the most common age-related dementias. We review each dementia within the context of a genes/environment continuum, with varying levels of genetic versus environmental influence. All major classes of dementia will be discussed but greatest attention will be given to the most common dementia, Alzheimer's disease, for which several new genetic factors were recently identified.
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