Modeling Hereditary spastic paraplegia in animal to reveal developmental pathology

Abstract

Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurodegenerative disorder with axon-length dependent dying-back of upper motor neuron in the corticospinal tract (CST). The average age of onset is 30.8 years old, but 11% of cases have been reported to be early-onset at age 0-5, suggesting developmental defects. To study developmental pathologies of early-onset HSP, we have developed animal models using in utero electroporation (IUE) by selectively introduced genetic variants found in human HSP cases to primary motor cortex targeting layer V pyramidal neurons, precursors of CST neurons. We were able to characterize morphological and cellular defects that might be relevant to early-onset HSP. Using previously reported early-onset HSP gene, including SPG3a (ATL1) and SPG4 (SPAST) as well as late-onset HSP, we will further utilize this approach to test novel variants found in early-onset HSP cases. This study would reveal developmental pathologies underlying early-onset HSP caused by novel genetic variants.