Hereditary spastic paraplegia (HSP) are a diverse group of genetic disorders characterized by lower limbs weakness and progressive spasticity which results from axon degeneration of upper motor neurons. Mutations in the SPAST gene (SPG4) is the most frequent autosomal dominant form with over than 300 mutations identified so far. SPAST codify for spastin, protein responsible for severing microtubules. Studies using motor neurons derived from patients showed that SPAST downregulation leads to the accumulation of axonal swellings, consequently causing the neurodegenerative phenotype observed in patients. We evaluated a large family with more than 40 individuals with pathogenic mutation in SPAST. However, about 20 individuals carrying the pathogenic mutation are very mildly or not affected (asymptomatic). The aims of the present project are to combine powerful genetic tools (SNP and expression microarray) to identify the chromosome region, the gene and genetic/epigenetic variants associated with HSP protection in individuals from the present family. We also intend to perform in vitro functional studies using motor neurons derived from iPSC from affected and asymptomatic patients as well as healthy relatives to evaluate motor neuron morphology and physiology related to neurodegeneration phenotype. Next, we intend to perform functional studies using the in vivo model of zebrafish rescuing the phenotype in knockdown fish for the spast gene, thus validating potential variants as neurodegeneration protectors.
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