title: Motor neurone disease/amyotrophic lateral sclerosis associated with intermediate-length CAG repeat expansions in Ataxin-2 does not have 1C2-positive polyglutamine inclusions.
abstract: Intermediate-length cytosine-adenine-guanine 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.
  
  
  
  Polymerase chain reaction and sequencing of DNA from frozen brain tissue on a cohort of 178 amyotrophic lateral sclerosis (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.
  
  
  
  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 neurone depletion, and three out of four cases had transactive response DNA binding protein 43 (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 neurones. Ataxin-2 staining was variable both within and between cases, but no staining pattern that was specific for cases with ATXN2 mutations was seen.
  
  
  
  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 neurones. There is no consistent histopathological hallmark that is unique to ATXN2-ALS.
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: John Robin
authors.initials: JR
authors.lastname: Highley
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Lorente Pons
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: Johnathan
authors.initials: J
authors.lastname: Cooper-Knock
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Wharton
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ince
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: Jon
authors.initials: J
authors.lastname: Wood
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: Janine
authors.initials: J
authors.lastname: Kirby
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology*; D000067698:Ataxin-2 / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion
chemical_list: C000593752:ATXN2 protein, human; D000067698:Ataxin-2; D010455:Peptides; C097188:polyglutamine
keywords: Ataxin-2; genetics; inclusion bodies; motor neurone disease; polyglutamine