Functional implications of paralog genes in polyglutamine spinocerebellar ataxias

AbstractPolyglutamine (polyQ) spinocerebellar ataxias (SCAs) comprise a group of autosomal dominant neurodegenerative disorders caused by (CAG/CAA)n expansions. The elongated stretches of adjacent glutamines alter the conformation of the native proteins inducing neurotoxicity, and subsequent motor and neurological symptoms. Although the etiology and neuropathology of most polyQ SCAs have been extensively studied, only a limited selection of therapies is available. Previous studies on SCA1 demonstrated thatATXN1L, a human duplicated gene of the disease-associatedATXN1, alleviated neuropathology in mice models. Other SCA-associated genes have paralogs (i.e., copies at different chromosomal locations derived from duplication of the parental gene), but their functional relevance and potential role in disease pathogenesis remain unexplored. Here, we review the protein homology, expression pattern, and molecular functions of paralogs in seven polyQ dominant ataxias —SCA1, SCA2, MJD/SCA3, SCA6, SCA7, SCA17, and DRPLA. BesidesATXN1L, we highlightATXN2L,ATXN3L,CACNA1B,ATXN7L1,ATXN7L2,TBPL2, andRERE as promising functional candidates to play a role in the neuropathology of the respective SCA, along with the parental gene. Although most of these duplicates lack the (CAG/CAA)n region, if functionally redundant, they may compensate for a partial loss-of-function or dysfunction of the wild-type genes in SCAs. We aim to draw attention to the hypothesis that paralogs of disease-associated ...

Source: Human Genetics - October 16, 2023 Category: Genetics & Stem Cells Source Type: research