Spinocerebellar Ataxia 36: From Mutations Toward Therapies

Abstract

Spinocerebellar ataxia 36 (SCA36) is a type of repeat expansion-related neurodegenerative disorder identified a decade ago. Like other SCAs, the symptoms of SCA36 include the loss of coordination like gait ataxia and eye movement problems, but motor neuron-related symptoms like muscular atrophy are also present in those patients. The disease is caused by a GGCCTG hexanucleotide repeat expansion in the gene Nop56, and the demographic incidence map showed that this disease was more common among the ethnic groups of Japanese and Spanish descendants. Although the exact mechanisms are still under investigation, the present evidence supports that the expanded repeats may undergo repeat expansion-related non-AUG-initiated translation, and these dipeptide repeat products could be one of the important ways to lead to pathogenesis. Such studies may help develop potential treatments for this disease.

Keywords: GGCCTG; RAN translation; SCA36; antisense oligos; motor neuron disease; repeat expansion disorders.

FIGURE 1

Structure of GGCCTG repeats and its surrounding sequences. The relative location of the repeat expansion in the Nop56 gene and the unconventional translation products from all reading frames on the sense transcript are shown. Exon 1 and exon 2 are shown as closed blue boxes, and the black solid line indicates the introns. The repeats are in red. The Nop56 start codon ATG (in green) and the two stop codons in frame of unconventional translation producing AW and GP dipeptide repeats are indicated with two asterisks (in red). The schematic of the Nop56 gene is drawn on scale with the 50 bp length showed on the right.

FIGURE 2

Possible mechanisms of pathogenesis in SCA36. Left panel (normal condition): in the nucleus, the short repeat-containing wild-type Nop56 genes (exon 1 and exon 2 in blue boxes, black solid line as introns, and GGCCTG repeats in red boxes) are transcribed into mature mRNAs (blue lines), and the repeat-containing introns spliced out as lariats (in black), other RNA-binding proteins (in brown) are scattered in the nucleus; in cytoplasm, Nop56 mature mRNAs are translated to normal amount Nop56 proteins (green ovals) and neurons are functioning normally. Right panel (SCA36 condition): in nucleus, the mutant Nop56 gene with expanded GGCCTG repeats (in red box) could be transcribed at different amounts (haploinsufficiency mechanism/1a), and the expanded GGCCUG repeat RNA (in red) could be either present as lariats or retained in mRNAs to sequester other RNA-binding proteins (RNA gain-of-function mechanism/2); in the cytoplasm, the expanded GGCCUG repeat-containing Nop56 mRNAs could either impede the production of NOP56 proteins (haploinsufficiency mechanism/1b) or undergo unconventional translation (RAN translation mechanism/3) into dipeptide repeat (DPR) proteins (red triangle, rectangle, circle, pentagon, and trapezoid). These possible mechanisms result in the impaired neuron functions ultimately.