title: Cerebellar neuronal loss in amyotrophic lateral sclerosis cases with ATXN2 intermediate repeat expansions.
abstract: OBJECTIVE
  Despite evidence suggesting that the cerebellum may be targeted in amyotrophic lateral sclerosis (ALS), particularly in cases with repeat expansions in the ATXN2 and C9ORF72 genes, the integrity of cerebellar neurons has yet to be examined. The present study undertakes a histopathological analysis to assess the impact of these repeat expansions on cerebellar neurons and determine whether similar cerebellar pathology occurs in sporadic disease.
  
  
  METHODS
  Purkinje and granule cells were quantified in the vermis and lateral cerebellar hemispheres of ALS cases with repeat expansions in the ATXN2 and C9ORF72 genes, sporadic disease, and sporadic progressive muscular atrophy with only lower motor neuron degeneration.
  
  
  RESULTS
  ALS cases with intermediate repeat expansions in the ATXN2 gene demonstrate a significant loss in Purkinje cells in the cerebellar vermis only. Despite ALS cases with expansions in the C9ORF72 gene having the highest burden of inclusion pathology, no neuronal loss was observed in this group. Neuronal numbers were also unchanged in sporadic ALS and sporadic PMA cases.
  
  
  CONCLUSIONS
  The present study has established a selective loss of Purkinje cells in the cerebellar vermis of ALS cases with intermediate repeat expansions in the ATXN2 gene, suggesting a divergent pathogenic mechanism independent of upper and lower motor neuron degeneration in ALS. We discuss these findings in the context of large repeat expansions in ATXN2 and spinocerebellar ataxia type 2, providing evidence that intermediate repeats in ATXN2 cause significant, albeit less substantial, spinocerebellar damage compared with longer repeats in ATXN2.
authors.affiliation: Neuroscience Research Australia, Sydney, Australia.|School of Medical Sciences, University of New South Wales, Sydney, Australia.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Tan
authors.affiliation: Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, Australia.
authors.forename: Jillian J
authors.initials: JJ
authors.lastname: Kril
authors.affiliation: Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, Australia.
authors.forename: Ciara
authors.initials: C
authors.lastname: McGinley
authors.affiliation: Neuroscience Research Australia, Sydney, Australia.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hassani
authors.affiliation: Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Masuda-Suzukake
authors.affiliation: Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, Australia.
authors.forename: Remika
authors.initials: R
authors.lastname: Mito
authors.affiliation: Brain and Mind Center, Sydney Medical School, The University of Sydney, Sydney, Australia.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Kiernan
authors.affiliation: Neuroscience Research Australia, Sydney, Australia.|School of Medical Sciences, University of New South Wales, Sydney, Australia.
authors.forename: Glenda M
authors.initials: GM
authors.lastname: Halliday
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology*; D000067698:Ataxin-2 / Q000235:genetics*; D000073885:C9orf72 Protein; D065814:Cerebellar Vermis / Q000473:pathology*; D042622:DNA Repeat Expansion; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011506:Proteins; D011689:Purkinje Cells / Q000473:pathology*; D014015:Tissue Banks
chemical_list: C000593752:ATXN2 protein, human; D000067698:Ataxin-2; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins