Genetic modeling of a neurodegenerative polyglutamine disorder in zebrafish and analysis of polyglutamine aggregate dynamics.

Polyglutamine (polyQ) diseases are a family of nine neurodegenerative disorders caused by an unstable CAG expansion in the respective genes. One polyQ disease, spinocerebellar ataxia type 3 (SCA-3) disease was modeled by stable overexpression of pathogenic C-terminal Atx-3 in zebrafish Purkinje cells. Zebrafish larvae expressing Atx-3 polyQ showed significant locomotion difficulties and eye movement impairments, displaying phenotypical characteristics for cerebellar dysfunction in patients. Therefore, this model can provide important insights into the mechanisms of SCA-3 pathogenesis and progression. SCA-1 is caused by polyQ mutation in Atx-1. The growth of Atx-1 aggregates can occur either from the direct recruitment of newly synthesized protein, or from fusion of two aggregates. It was concluded that nuclear Actin is involved in Atx-1 aggregation dynamics, substantiated by the colocalization of both proteins and colocalization with the Actin depolymerizing factor Cofilin-1. Thus, these findings can lay a foundation to understand the molecular mechanisms of SCA-1