Chapter 34 - HDL2 Mouse

Abstract

In 2001, Margolis and colleagues described a new autosomal dominant neurodegenerative disease, Huntington disease–like 2 (HDL2), associated with a CAG/CTG repeat expansion in an alternatively spliced exon of junctophilin 3 that encodes junctophilin 3. HDL2 is a genocopy of Huntington disease (HD)—the genetic, clinical, and neuropathological features of the two diseases are similar. Although overwhelming evidence supports the hypothesis that gain-of-toxic function of expanded polyglutamine is central to HD pathogenesis, HDL2 does not appear to be primarily a polyglutamine disease. Instead, evidence from cell, animal, and human postmortem tissue indicates that HDL2 pathogenesis is multifactorial and includes gain- and loss-of-function mechanisms involving transcripts and their protein products, generated from both strands of the HDL2 locus. The similarity between HD and HDL2 suggest that HD pathogenesis may also include multitranscript, bidirectional aspects, and that looking for points of convergence between HD and HDL2 may help us to elucidate the pathogeneses of both disorders.