Motor neurone disease/amyotrophic lateral sclerosis associated with intermediate length CAG repeat expansions in Ataxin-2 does not have 1C2-positive polyglutamine inclusions.

BACKGROUND: Intermediate length CAG repeat expansions in the ATXN2 gene (which encodes for Ataxin-2 protein) have been linked to increased risk for motor neurone disease/amyotrophic lateral sclerosis (ALS). We screened DNA from cases for which we had post mortem brain tissue to enable characterization of the neuropathology associated with this mutation. METHODS: PCR and sequencing of DNA from frozen brain tissue on a cohort of 178 ALS autopsy cases from the north of England and 159 controls was performed. This was followed by tinctorial staining and immunohistochemistry (including for Ataxin-2) on selected blocks from ALS cases with intermediate length expansions (ATXN2-ALS), sporadic ALS cases and neurologically healthy controls. RESULTS: Four ALS cases with intermediate length CAG repeat expansions within ATXN2 were identified. One such case also had a mutation of the C9ORF72 gene. All had lower motor neuron depletion, and 3 out of 4 cases had TDP-43-positive neuronal cytoplasmic inclusions (predominantly skein-like). No inclusions of aggregated polyglutamine proteins were identified. Ataxin-2 protein expression was largely granular and cytoplasmic with the most prominent staining observed in larger neurons. Ataxin-2 staining was variable both within and between cases, but no staining pattern that was specific for cases with ATXN2 mutations was seen. CONCLUSIONS: Intermediate expansions of the CAG repeat in ATXN2 are associated with ALS. They are mostly associated with TDP-43 proteinopathy, but not with 1C2-positive polyglutamine inclusions. In the nervous system, Ataxin-2 protein expression is predominantly seen in large neurons. There is no consistent histopathological hallmark that is unique to ATXN2-ALS.