Increased Karyopherin Alpha Levels Attenuate Mutant Ataxin-1-Induced Neurodegeneration

Abstract

AbstractNeurodegenerative diseases are characterized by the abnormal accumulation of disease-driving proteins. Emerging evidence suggests that nucleocytoplasmic transport (NCT) components play a critical role in neurodegeneration. This study investigates the impact of modulating Karyopherin alpha (KPNA) levels on neurodegeneration induced by mutant Ataxin-1 (ATXN1) using aDrosophilamodel of Spinocerebellar Ataxia Type 1 (SCA1). Our findings reveal that ATXN1 (82Q) interacts with KPNAs in the nucleus and cytoplasm of neurons. Increasing KPNA levels alleviates ATXN1 (82Q)-induced neurodegeneration and progressive neuronal dysfunction. Surprisingly, mechanistic analyses demonstrate that elevated KPNA levels retain mutant ATXN1 in the cytoplasm, reducing its nuclear accumulation in theDrosophilacentral nervous system. Moreover, elevated KPNA levels lead to a decrease in soluble oligomeric ATXN1. These results indicate that KPNAs may act as chaperones for mutant ATXN1, preventing its nuclear translocation and reducing its pathological effects. Importantly, they also constitute a proof of principle that retaining mutant ATXN1 in the cytoplasm represents an attractive and viable therapeutic option. Given the dysregulation of Karyopherins in many neurodegenerative diseases and their emerging role as chaperones, the results presented here may extend beyond SCA1 into other disorders like Alzheimer’s or Parkinson’s disease.