Applying mouse embryo model for developmental pathology of hereditary spastic paraplegia

Abstract

Hereditary spastic paraplegia (HSP) is a group of genetically heterogeneous neurodegeneration disease that shows progressive dying back of upper motor neurons that consist corticospinal tract (CST). HSP has a wide age of onset spectrum and onset at 0~5 occupy 11% of HSP cases. Regarding average onset is 30.8 years old, these early onset HSP cases imply significant developmental defects that are different with late-onset HSP cases. Thus we were trying to broaden our understanding about developmental pathology of early-onset HSP by mouse embryo study. Using in utero electroporation (IUE), we could transfer human gene variants already known to cause early-onset HSP, like SPG3a (ATL1) and SPG4 (SPAST) to the precursor of upper motor neurons that are located in the layer V primary motor cortex. These mouse embryo models suggest cell morphology of developmental stage under HSP gene variants. Furthermore, it would suggest developing defects of axon in HSP, including axon fasciculation and projection reported to be critical in other motor neuron disease. 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.