HUNTINGTON’S DISEASE: GENETIC MODIFIERS OF AGE AT ONSET AND PATHOLOGICAL BIOMARKERS

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease, clinically characterized by movement disorders, cognitive deficits, and psychiatric problems. HD is caused by the expansion of a CAG repeat within exon 1 of IT15 gene. HD exhibits the typical phenomenon of genetic anticipation and the symptoms of the disease appear earlier and more severe in subsequent generations due to meiotic instability. The onset of HD is conventionally defined as motor onset although cognitive and psychiatric impairments may precede choreic movements or other movements disorders. The relationship between CAG repeats number and motor onset is well-known in HD; little is reported about the correlations between CAG repeats and non-motor onset. In the first part of this PhD thesis, we aimed to investigate the dependence of motor, cognitive and psychiatric onsets from expanded CAG repeat length and to study the correlation among these several modalities of clinical debut in a cohort of 188 patients with HD. We found that psychiatric and motor problems often represented the first symptoms of the disease, alone or in combination. The isolate cognitive onset was very rare. Lower but always consistent correlations were present between psychiatric onset and motor onset and between cognitive onset and psychiatric onset. Among the different psychiatric symptoms, Perseverative/Obsessive Behaviour and Apathy showed considerable positive correlation levels with motor and cognitive onsets. We evidenced that cognitive onset can depend from CAG repeats in IT15 pathological allele: in our cohort, the length accounts for the 54% of variability in age at cognitive onset. The CAG repeat accounts only for approximately 56%-70% of the variation in age at onset in HD. It is therefore possible to imagine that modifier genetic variations, that segregate independently from the primary mutation, could influence the age at onset. In the second part of this PhD thesis, we decided to study seven SCAs genes (ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, PPP2R2B, and TBP) as modifiers of age at onset in HD due to genetic, pathological, and clinical similarities between HD and SCAs. Our study did not find extensive correlations between CAG repeats in SCA genes and age at onset of HD. The only exceptions are represented by ATXN2 and CACNA1 for age at motor onset, and ATXN2 for age at psychiatric onset. When a multiple regression model was formulated and when the age at motor onset was considered, a small additional effect was identified only for CACNA1A. CAG repeats in expanded IT15 and larger CACNA1A alleles account for 64% of age at motor onset in HD patients. In the last part of this PhD thesis, we designed a clinical study to measure the expression levels of MAP1LC3, SQSTM1 and WDFY3 in 20 patients with HD, and to compare these levels with those found in healthy controls and patients suffering from SCA 2 (spino-cerebellar ataxia type 2), another polyglutamine repeat disorder. MAP1LC3, SQSTM1 and WDFY3 genes seem to have a critical role in aggrephagy and aggrephagy levels are reported pathologically increased in HD patients. We measured expression levels in peripheral blood mononuclear cells as they represent an easily accessible and repeatable matrix for clinical use such as clinical trials or observational studies. MAP1LC3B, SQSTM1, and WDFY3 were all increased in HD patients, suggesting a profound and intense induction in autophagy, aimed at counteracting the formation of protein aggregates. In contrast, SCA2 patients had a more modest modification with higher expression levels of WDFY3 alone.