Molecular Pathogenesis in Huntington’s Disease

Aktuelle Neurologie, 2004

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the IT-15 gene; however, it remains unknown how the mutation leads to selective neurodegeneration. Several lines of evidence suggest impaired mitochondrial function as a component of the neurodegenerative process in HD. We assessed energy metabolism in the skeletal muscle of 15 HD patients and 12 asymptomatic mutation carriers in vivo using 31 P magnetic resonance spectroscopy. Phosphocreatine recovery after exercise is a direct measure of ATP synthesis and was slowed significantly in HD patients and mutation carriers in comparison to age-and gender-matched healthy controls. We found that oxidative function is impaired to a similar extent in manifest HD patients and asymptomatic mutation carriers. Our findings suggest that mitochondrial dysfunction is an early and persistent component of the pathophysiology of HD.

Human Molecular Genetics, 2011

The purpose of our study was to determine the relationship between mutant huntingtin (Htt) and mitochondrial dynamics in the progression of Huntington's disease (HD). We measured the mRNA levels of electron transport chain genes, and mitochondrial structural genes, Drp1 (dynamin-related protein 1), Fis1 (fission 1), Mfn1 (mitofusin 1), Mfn2 (mitofusin 2), Opa1 (optric atrophy 1), Tomm40 (translocase of outermembrane 40) and CypD (cyclophilin D) in grade III and grade IV HD patients and controls. The mutant Htt oligomers and the mitochondrial structural proteins were quantified in the striatum and frontal cortex of HD patients. Changes in expressions of the electron transport chain genes were found in HD patients and may represent a compensatory response to mitochondrial damage caused by mutant Htt. Increased expression of Drp1 and Fis1 and decreased expression of Mfn1, Mfn2, Opa1 and Tomm40 were found in HD patients relative to the controls. CypD was upregulated in HD patients, and this upregulation increased as HD progressed. Significantly increased immunoreactivity of 8-hydroxy-guanosine was found in the cortical specimens from stage III and IV HD patients relative to controls, suggesting increased oxidative DNA damage in HD patients. In contrast, significantly decreased immunoreactivities of cytochrome oxidase 1 and cytochrome b were found in HD patients relative to controls, indicating a loss of mitochondrial function in HD patients. Immunoblotting analysis revealed 15, 25 and 50 kDa mutant Htt oligomers in the brain specimens of HD patients. All oligomeric forms of mutant Htt were significantly increased in the cortical tissues of HD patients, and mutant Htt oligomers were found in the nucleus and in mitochondria. The increase in Drp1, Fis1 and CypD and the decrease in Mfn1 and Mfn2 may be responsible for abnormal mitochondrial dynamics that we found in the cortex of HD patients, and may contribute to neuronal damage in HD patients. The presence of mutant Htt oligomers in the nucleus of HD neurons and in mitochondria may disrupt neuronal functions. Based on these findings, we propose that mutant Htt in association with mitochondria imbalance and mitochondrial dynamics impairs axonal transport of mitochondria, decreases mitochondrial function and damages neurons in affected brain regions of HD patients. *

Human Molecular Genetics, 2013

Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of a CAG repeat encoding a polyglutamine tract in the huntingtin (Htt) protein. The mutation leads to neuronal death through mechanisms which are still unknown. One hypothesis is that mitochondrial defects may play a key role. In support of this, the activity of mitochondrial complex II (C-II) is preferentially reduced in the striatum of HD patients. Here, we studied C-II expression in different genetic models of HD expressing N-terminal fragments of mutant Htt (mHtt). Western blot analysis showed that the expression of the 30 kDa Iron-Sulfur (Ip) subunit of C-II was significantly reduced in the striatum of the R6/1 transgenic mice, while the levels of the FAD containing catalytic 70 kDa subunit (Fp) were not significantly changed. Blue native gel analysis showed that the assembly of C-II in mitochondria was altered early in N171-82Q transgenic mice. Early loco-regional reduction in C-II activity and Ip protein expression was also demonstrated in a rat model of HD using intrastriatal injection of lentiviral vectors encoding mHtt. Infection of the rat striatum with a lentiviral vector coding the C-II Ip or Fp subunits induced a significant overexpression of these proteins that led to significant neuroprotection of striatal neurons against mHtt neurotoxicity. These results obtained in vivo support the hypothesis that structural and functional alterations of C-II induced by mHtt may play a critical role in the degeneration of striatal neurons in HD and that mitochondrial-targeted therapies may be useful in its treatment.

Journal of Bioenergetics and Biomembranes, 2010

Huntington Disease (HD) is a relatively common inherited neuropathy with characteristic cognitive and behavioral features. HD usually has a late onset and often is not recognized until the third or fourth decades of life. Transmitted as an autosomal dominant trait, HD has become a prototype for understanding a group of neurogenetic disorders. As a class, HD and the others are manifestations of the expansion of a trinucleotide repeat within the gene coding or structural region. In HD expansion of the (CAG) n repeat in the first exon from an average of 18 (normal) to a median of 44 is the underlying molecular biologic change. In affected individuals, the mutant HD protein (Huntingtin, mHtt) thus contains an extended polyglutamine repeat. Clinical and neuropathic changes in the caudate and putamen nuclei occur relatively early with other brain regions being affected later. Mitochondrial structure, altered electron transport and increased brain lactate levels have implicated mitochondria in HD pathophysiology. There is also evidence that reduced transcription of the peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) leads to altered downstream gene regulation. Further evidence for mitochondrial involvement is presented in the following reviews. Clarifying mitochondrial derangements has led to some possibilities for therapeutic intervention.

BioFactors, 2011

Huntington's disease (HD) is an inherited autosomal, progressive neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive impairments and psychiatric disturbances. HD is caused by an abnormal expansion of a CAG region located in exon 1 of the gene encoding the huntingtin protein (Htt) and is the causative factor in the pathogenesis of HD. However, recent evidences show that impaired mitochondrial function plays a key role in the pathogenic processes of the desease. The underlying mechanisms by which mutant Htt (mHtt) causes HD have not been fully elucidated, however mutant Htt can impair mitochondrial function by dysregulation of transcriptional processes, calcium dyshomeostasis, and defective mitochondrial bioenergetics. Mutant Htt induce intracellular Ca 2+ in neurons affected by HD and increased intracellular Ca 2+ excessively enter mitochondria and induce to open the mitochondrial permeability transition pores (mPTP), leading to decreased mitochondrial ATP, and neuronal death. Transcriptional processes regulated by peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α), which are critical for mitochondrial biogenesis, have also been shown to be impaired in HD. This review article discusses current developments, in determining the role of mitochondrial morphological and functional abnormalities contributing to the pathogenesis of HD and also discusses the current other possible therapeutic interventions.

Cell Death and Disease, 2011

Prion, 2013

BMC Biochemistry, 2007

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2010

Huntington's disease (HD) is an inherited progressive neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits and psychiatric disturbances. The disease is caused by an abnormal expansion of a CAG repeat located in exon 1 of the gene encoding the huntingtin protein (Htt) that confers a toxic function to the protein. The most striking neuropathological change in HD is the preferential loss of medium spiny GABAergic neurons in the striatum. The mechanisms underlying striatal vulnerability in HD are unknown, but compelling evidence suggests that mitochondrial defects may play a central role. Here we review recent findings supporting this hypothesis. Studies investigating the toxic effects of mutant Htt in cell culture or animal models reveal mitochondrial changes including reduction of Ca 2+ buffering capacity, loss of membrane potential, and decreased expression of oxidative phosphorylation (OXPHOS) enzymes. Striatal neurons may be particularly vulnerable to these defects. One hypothesis is that neurotransmission systems such as dopamine and glutamate exacerbate mitochondrial defects in the striatum. In particular, mitochondrial dysfunction facilitates impaired Ca 2+ homeostasis linked to the glutamate receptor-mediated excitotoxicity. Also dopamine receptors modulate mutant Htt toxicity, at least in part through regulation of the expression of mitochondrial complex II. All these observations support the hypothesis that mitochondria, acting as "sensors" of the neurochemical environment, play a central role in striatal degeneration in HD.