Isoform-paralog specificity and tissue-dependent vulnerabilities in neurological disorders

A long-standing observation in studies of neurological disorders is that broadly expressed disease genes can cause dysfunctions that are limited to certain brain regions or cell types. In this issue of Genes & Development, Lee et al. (doi:10.1101/gad.353596.125) address the mystery of this selective vulnerability by studying ATXN1-CIC interactions implicated in spinocerebellar ataxia type 1. They provide compelling evidence that specific ATXN1 paralogs preferentially interact with specific CIC isoforms tissue-dependently. Whereas ATXN1-CIC-L complexes regulate hippocampal gene expression and learning, ATXN1L-CIC-S complexes regulate lung alveolarization, postnatal survival, and hydrocephalus risk. This work thus demonstrates the potential contribution of isoform-paralog specificity to tissue-specific vulnerabilities in neurological disorders.