Amyloid precursor-like protein 2 cleavage contributes to neuronal intranuclear inclusions and cytotoxicity in spinocerebellar ataxia-7 (SCA7)

In spinocerebellar ataxia-7 (SCA7), a polyglutamine (polyQ) expansion in the ataxin-7 protein leads to the formation of neuronal intranuclear inclusions (NIIs) and neurodegeneration. In this study, amyloid precursor-like protein 2 (APLP2) was identified as a partner protein for ataxin-7. APLP2, belonging to the APP gene family, undergoes secretase and caspase cleavages and has been implicated in the pathogenesis of Alzheimer's disease (AD). Activated caspase-3 cleaves APP family proteins to release N-terminal fragments (NTFs) and intracellular C-terminal domains (ICDs), which can translocate into the nucleus and induce neurotoxicity in AD. Here, we report abnormal nuclear relocation of APLP2 and detection of NTFs in NIIs in SCA7. The ICDs generated by caspase-3 cleavage of APLP2 accumulate in nuclei and contribute to a cumulative toxicity when coexpressed with mutated ataxin-7. Our data suggest that the interaction between APLP2 and ataxin-7 and proteolytic processing of APLP2 may contribute to the pathogenesis of SCA7.

Research Highlights
► Ataxin-7, the gene product of SCA7, interacts with APLP2.
► Caspase-3 cleavage of APLP2 can be enhanced in SCA7.
► N-terminal fragments of APLP2 are entrapped in nuclear aggregates in SCA7.
► Nuclear accumulation of C-terminal domains of APLP2 contributes to neurotoxicity in SCA7.