Cerebellar neuronal loss in amyotrophic lateral sclerosis cases with ATXN2 intermediate repeat expansions
Rachel H Tan PhD
Neuroscience Research Australia, Sydney, Australia
School of Medical Sciences, University of New South Wales, Sydney, Australia
Search for more papers by this authorJillian J Kril PhD
Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, Australia
Search for more papers by this authorCiara McGinley BSc
Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, Australia
Search for more papers by this authorMohammad Hassani BSc(Hons)
Neuroscience Research Australia, Sydney, Australia
Search for more papers by this authorMasami Masuda-Suzukake PhD
Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
Search for more papers by this authorMasato Hasegawa PhD
Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
Search for more papers by this authorRemika Mito BSc(Hons)
Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, Australia
Search for more papers by this authorMatthew C Kiernan DSc, FRACP
Brain and Mind Center, Sydney Medical School, The University of Sydney, Sydney, Australia
Search for more papers by this authorCorresponding Author
Glenda M Halliday PhD
Neuroscience Research Australia, Sydney, Australia
School of Medical Sciences, University of New South Wales, Sydney, Australia
Address correspondence to Prof Glenda M. Halliday, Neuroscience Research Australia, Barker Street, Randwick, NSW 2031, Australia. E-mail [email protected]Search for more papers by this authorRachel H Tan PhD
Neuroscience Research Australia, Sydney, Australia
School of Medical Sciences, University of New South Wales, Sydney, Australia
Search for more papers by this authorJillian J Kril PhD
Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, Australia
Search for more papers by this authorCiara McGinley BSc
Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, Australia
Search for more papers by this authorMohammad Hassani BSc(Hons)
Neuroscience Research Australia, Sydney, Australia
Search for more papers by this authorMasami Masuda-Suzukake PhD
Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
Search for more papers by this authorMasato Hasegawa PhD
Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
Search for more papers by this authorRemika Mito BSc(Hons)
Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, Australia
Search for more papers by this authorMatthew C Kiernan DSc, FRACP
Brain and Mind Center, Sydney Medical School, The University of Sydney, Sydney, Australia
Search for more papers by this authorCorresponding Author
Glenda M Halliday PhD
Neuroscience Research Australia, Sydney, Australia
School of Medical Sciences, University of New South Wales, Sydney, Australia
Address correspondence to Prof Glenda M. Halliday, Neuroscience Research Australia, Barker Street, Randwick, NSW 2031, Australia. E-mail [email protected]Search for more papers by this authorAbstract
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.
Interpretation
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. Ann Neurol 2016;79:295–305
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