Papers by Ferdinando Squitieri
CNS Neuroscience & Therapeutics, 2016
Immune dysfunction, promoted by pro-inflammatory cytokines, plays a pivotal role in neurodegenera... more Immune dysfunction, promoted by pro-inflammatory cytokines, plays a pivotal role in neurodegeneration associated with Huntington's disease. The aim of this study was to investigate the emerging immunoregulatory and antiinflammatory properties of Sertoli cells in Huntington's disease. The experimental R6/2 mouse model of Huntington's disease was treated by a single intraperitoneal injection of microencapsulated prepubertal porcine Sertoli cells and lifespan, motor performance and striatal inflammatory pattern have been evaluated. The results of this study demonstrated that a single intraperitoneal injection of microencapsulated prepubertal porcine Sertoli cells uniquely improved performances and extended the life expectancy of R6/2 Huntington's disease mice, by immune dysfunction modulation in brain. This study highlights the immunomodulatory and trophic role of Sertoli cells that could be of help in the treatment of neurodegenerative disorders.
Journal of Neurology, Neurosurgery & Psychiatry, 2010
Drug Design, Development and Therapy, 2015
Huntington disease (HD) is a chronic, genetic, neurodegenerative disease for which there is no cu... more Huntington disease (HD) is a chronic, genetic, neurodegenerative disease for which there is no cure. The main symptoms of HD are abnormal involuntary movements (chorea and dystonia), impaired voluntary movements (ie, incoordination and gait balance), progressive cognitive decline, and psychiatric disturbances. HD is caused by a CAG-repeat expanded mutation in the HTT gene, which encodes the huntingtin protein. The inherited mutation results in the production of an elongated polyQ mutant huntingtin protein (mHtt). The cellular functions of the Htt protein are not yet fully understood, but the functions of its mutant variant are thought to include alteration of gene transcription and energy production, and dysregulation of neurotransmitter metabolism, receptors, and growth factors. The phenylpiperidines pridopidine (4-[3-methanesulfonyl-phenyl]-1-propyl-piperidine; formerly known as ACR16) and OSU6162 ([S]-[-]-3-[3-methane [sulfonyl-phenyl]-1-propyl-piperidine) are members of a new class of pharmacologic agents known as "dopamine stabilizers". Recent clinical trials have highlighted the potential of pridopidine for symptomatic treatment of patients with HD. More recently, the analysis of HD models (ie, in vitro and in mice) highlighted previously unknown effects of pridopidine (increase in brain-derived neurotrophic factor, reduction in mHtt levels, and σ-1 receptor binding and modulation). These additional functions of pridopidine suggest it might be a neuroprotective and disease-modifying drug. Data from ongoing clinical trials of pridopidine will help define its place in the treatment of HD. This commentary examines the available preclinical and clinical evidence regarding the use of pridopidine in HD.
Journal of Huntington's Disease, 2015
AbstractBackground: Huntington&am... more AbstractBackground: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder leading to progressive motor, cognitive and functional decline. Antidopaminergic medications (ADMs) are frequently used to treat chorea and behavioural disturbances in HD. We aimed to assess how the use of such medications was associated with the severity and progression of the motor aspects of the condition, given that there have been concerns that such drugs may actually promote neurological deterioration. Using multiple linear regression, supplemented by principal component analysis to explore the overall correlation patterns and help identify relevant covariates, we assessed severity and progression of motor symptoms and functional decline in 651 manifest patients from the REGISTRY cohort followed for two years. ADM treated versus non-treated subjects were compared with respect to motor impairment at baseline and progression rate by means of multiple regression, adjusting for CAG-repeat and age. Patients treated with ADMs had significantly worse motor scores with greater functional disability at their first visit. They also showed a higher annual rate of progression of motor signs and disability over the next two years. In particular the rate of progression for oculomotor symptoms and bradykinesia was markedly increased whereas the rate of progression of chorea and dystonia was similar for ADM and drug naïve patients. These differences in clinical severity and progression could not be explained by differences in disease burden, duration of disease or other possible prognostic factors. The results from this analysis suggest ADM treatment is associated with more advanced and rapidly progressing HD although whether these drugs are causative in driving this progression requires further, prospective studies.
Journal of Cellular and Molecular Medicine, 2015
Huntington disease (HD) is a neurodegenerative disorder for which new treatments are urgently nee... more Huntington disease (HD) is a neurodegenerative disorder for which new treatments are urgently needed. Pridopidine is a new dopaminergic stabilizer, recently developed for the treatment of motor symptoms associated with HD. The therapeutic effect of pridopidine in patients with HD has been determined in two double-blind randomized clinical trials, however, whether pridopidine exerts neuroprotection remains to be addressed. The main goal of this study was to define the potential neuroprotective effect of pridopidine, in HD in vivo and in vitro models, thus providing evidence that might support a potential disease-modifying action of the drug and possibly clarifying other aspects of pridopidine mode-of-action. Our data corroborated the hypothesis of neuroprotective action of pridopidine in HD experimental models. Administration of pridopidine protected cells from apoptosis, and resulted in highly improved motor performance in R6/2 mice. The anti-apoptotic effect observed in the in vitro system highlighted neuroprotective properties of the drug, and advanced the idea of sigma-1-receptor as an additional molecular target implicated in the mechanism of action of pridopidine. Coherent with protective effects, pridopidine-mediated beneficial effects in R6/2 mice were associated with an increased expression of pro-survival and neurostimulatory molecules, such as brain derived neurotrophic factor and DARPP32, and with a reduction in the size of mHtt aggregates in striatal tissues. Taken together, these findings support the theory of pridopidine as molecule with disease-modifying properties in HD and advance the idea of a valuable therapeutic strategy for effectively treating the disease.
Value in Health, 2011
ABSTRACT Of these patients, the average (standard deviation) age was 57 (11) years in France and ... more ABSTRACT Of these patients, the average (standard deviation) age was 57 (11) years in France and 54 (12) years in Italy. The proportion of patients who were female was 50% and 53%, respectively. • Using data from these patients, the content validity of the H-CSRI was assessed and it was decided that certain items in the H-CSRI should be removed. – Four items relating to balance were removed from the motor subscale because they correlated strongly with other items (e.g. poor balance arises as a consequence of other impairments in motor function). – The item 'I could shop for groceries without help' was removed from the functional subscale because the item characteristic curve suggested that including this item added no extra information (see Figure 1). – In the behavioural subscale, the item 'Within the past month, how often has your relative not recognized familiar people?' was removed because it did not meet construct validity criteria. Figure 1. Item characteristic curves. The curves show the probability of a positive response to an item as a function of the functional ability of the respondent. Auto, automobile (car); employ, employment.
Background. Huntington disease (HD) mutation increases gain-of-toxic functions contributing to gl... more Background. Huntington disease (HD) mutation increases gain-of-toxic functions contributing to glutamate-mediated excitotoxicity. Riluzole interferes with glutamatergic neurotransmission, thereby reducing excitotoxicity, enhancing neurite formation in damaged motoneurons and increasing serum concentrations of BDNF, a brain cortex neurotrophin protecting striatal neurons from degeneration. Methods. We analyzed metabolic and volumetric differences in distinct brain areas of 23 subjects (12 affected vs. 11 healthy controls) by magnetic-resonance-imaging (MRI) and [fluorine-18]-fluoro-2-deoxyglucose (FDG) positron-emission-tomography (PET) scanning, according to fully automated protocols. Results. Untreated patients showed significantly greater proportional volume loss of gray matter and metabolic reduction than patients treated with riluzole in all cortical areas (p<0.05). The decreased rate of glucose metabolism correlated with worsening clinical scores in untreated patients, compa...
Background. We studied the anatomic and functional changes in various brain areas during the cour... more Background. We studied the anatomic and functional changes in various brain areas during the course of Huntington’s disease (HD) in a large cohort of mutation-positive individuals (n=71) encompassing the complete range of disability (presymptomatic through stage V), and in healthy controls, for the purpose of defining both degenerative and dysfunctional brain changes in the same subjects. Methods: We used an MRI and unsupervised multiparametric segmentation procedure based on a relaxometric approach to measure in vivo brain volumes in 71 subjects with presymptomatic to advanced HD. The same population was evaluated by 18F-FDG PET to assess variations in brain glucose metabolism. To predict age at onset in unaffected mutation carriers, we considered the estimated number of years from each subject’s age to manifested HD symptoms, for a given expanded triplet number. Results: Age-adjusted analyses confirmed that the 71 subjects as a group, as well as the subgroup of 24 unaffected presy...
Acta neurologica, 1989
We report a clinical survey of 82 patients with benign essential tremor (ET). Sixty five patients... more We report a clinical survey of 82 patients with benign essential tremor (ET). Sixty five patients had a positive family history. Onset age showed two peaks before 20 years and in the sixth decade. Segregation analysis confirmed an autosomal dominant inheritance. Head tremor occurred mainly in aged women, mental symptoms occurred mainly in subjects with a low onset age and a disabling tremor. An early onset age was not related to paternal or maternal transmission. In one family ET was associated with retinitis pigmentosa and ichthyosis.
Rivista di neurologia
This study concerns an analysis of outpatients seen at a Regional Clinic for Extrapyramidal and C... more This study concerns an analysis of outpatients seen at a Regional Clinic for Extrapyramidal and Cerebellar Disorders during the period 1974-1984. The main findings to emerge from this study are: 1) a predominance of males; 2) peak attendance figures correlated with precise factors; 3) the geographic origin of patients reflected the distance from the Regional Clinic and the relationship between local physicians and physicians at the Regional Clinic. Lastly, this epidemiological study has led to improvements in specific protocols for the management of the long-term outpatient, and to an increase in the number of patients attending the Center.
Acta neurologica
Since 1979 data about Huntington's Disease (HD) in Campania, a region of Southern Italy, has ... more Since 1979 data about Huntington's Disease (HD) in Campania, a region of Southern Italy, has been collecting. The prevalence of HD in this sample is 30.3 x 10(-6) (115 pedigrees, 1470 individuals). Mean age at onset was 38.67 years and the juvenile (onset before 20 years) accounted for 5.8%. Genetic linkage analysis in 4 unrelated pedigrees with D4S10 and D4S95 DNA probes has been performed. The absence of genetic heterogeneity--already proposed in a cooperative study for one pedigree--has been confirmed in this study.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2006
We studied the anatomic and functional changes in various brain areas during the course of Huntin... more We studied the anatomic and functional changes in various brain areas during the course of Huntington's disease (HD) in a large cohort of mutation-positive individuals (n = 71) encompassing the complete range of disability (presymptomatic through stage V), and in healthy controls, for the purpose of defining both degenerative and dysfunctional brain changes in the same subjects. We used an MRI and unsupervised multiparametric segmentation procedure based on a relaxometric approach to measure in vivo brain volumes in 71 subjects with presymptomatic to advanced HD. The same population was evaluated by 18F-FDG PET to assess variations in brain glucose metabolism. To predict age at onset in unaffected mutation carriers, we considered the estimated number of years from each subject's age to manifested HD symptoms, for a given expanded triplet number. Age-adjusted analyses confirmed that the 71 subjects as a group, as well as the subgroup of 24 unaffected presymptomatic subjects a...
Mechanisms of Ageing and Development, 2006
Huntington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;am... more Huntington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (HD) is caused by mutated huntingtin (htt), a toxic protein ubiquitously expressed in nervous and non-nervous system tissues. Fragmentation of htt by caspases and further accumulation in cells of protein aggregates contribute to cell dysfunction and death. In the attempt to elucidate whether this mechanism depends on patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; genotype, we analysed the pattern of htt fragmentation, the caspase 3, 8 and 9 activities and their variation in lymphoblasts with heterozygous and homozygous CAG mutation and in controls. Cells homozygous for expanded mutation showed greater amount of mutated fragments than heterozygotes and controls, caspase 3, 8 and 9 activities greater in mutated than control cell lines, after cyanide treatment, the caspase 3 and 8 particularly increased in homozygotes. This data offers a biological explanation to the clinical in-patients evidence of mutation homozygosity associated with more severe phenotype.
PLoS Currents, 2012
Conclusions Ack nowledgements Funding informationCompeting interests ReferencesAbstract Backgroun... more Conclusions Ack nowledgements Funding informationCompeting interests ReferencesAbstract Background: The clinical presentation of Juvenile Huntington s Disease (JHD) can be very different from adult-onset HD with little evidence to guide symptomatic management. Aim: To survey the current use of pharmacological treatments for JHD. Methods: Patients were identified through the HD Association, Hospital Doctors and the European Huntington s Disease Network REGISTRY study.
Nature, 2017
Nine neurodegenerative diseases are caused by expanded polyglutamine (polyQ) tracts in different ... more Nine neurodegenerative diseases are caused by expanded polyglutamine (polyQ) tracts in different proteins, such as huntingtin in Huntington&amp;amp;#39;s disease and ataxin 3 in spinocerebellar ataxia type 3 (SCA3). Age at onset of disease decreases with increasing polyglutamine length in these proteins and the normal length also varies. PolyQ expansions drive pathogenesis in these diseases, as isolated polyQ tracts are toxic, and an N-terminal huntingtin fragment comprising exon 1, which occurs in vivo as a result of alternative splicing, causes toxicity. Although such mutant proteins are prone to aggregation, toxicity is also associated with soluble forms of the proteins. The function of the polyQ tracts in many normal cytoplasmic proteins is unclear. One such protein is the deubiquitinating enzyme ataxin 3 (refs 7, 8), which is widely expressed in the brain. Here we show that the polyQ domain enables wild-type ataxin 3 to interact with beclin 1, a key initiator of autophagy. This interaction allows the deubiquitinase activity of ataxin 3 to protect beclin 1 from proteasome-mediated degradation and thereby enables autophagy. Starvation-induced autophagy, which is regulated by beclin 1, was particularly inhibited in ataxin-3-depleted human cell lines and mouse primary neurons, and in vivo in mice. This activity of ataxin 3 and its polyQ-mediated interaction with beclin 1 was competed for by other soluble proteins with polyQ tracts in a length-dependent fashion. This competition resulted in impairment of starvation-induced autophagy in cells expressing mutant huntingtin exon 1, and this impairment was recapitulated in the brains of a mouse model of Huntington&amp;amp;#39;s disease and in cells from patients. A similar phenomenon was also seen with other polyQ disease proteins, including mutant ataxin 3 itself. Our data thus describe a specific function for a wild-type polyQ tract that is abrogated by a competing longer polyQ mutation in a disease protein, and identify a deleterious function of such mutations distinct from their propensity to aggregate.
Neurotherapeutics, 2010
... F. Squitieri 1 , M. Cannella 1 , M. Simonelli 1 , T. Martino 1 , C. Colonnese 1 and A. Ciarmi... more ... F. Squitieri 1 , M. Cannella 1 , M. Simonelli 1 , T. Martino 1 , C. Colonnese 1 and A. Ciarmiello 2. 1 IRCCS Neuromed, Pozzilli (IS), Italy. 2 Sant'Andrea Hospital, La Spezia, Italy. Available online 1 January 2010. Background. Searching ...
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Papers by Ferdinando Squitieri