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Acta Neuropathol. 2015 Oct;130(4):559-73. doi: 10.1007/s00401-015-1474-4. Epub 2015 Sep 8.

Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers.

Author information

1
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
2
Mayo Graduate School, Mayo Clinic, Rochester, MN, 55905, USA.
3
Ludwig Institute, University of California at San Diego, La Jolla, CA, 92093, USA.
4
Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, 32224, USA.
5
Department of Neurology, Mayo Clinic, Jacksonville, FL, 32224, USA.
6
Section of Biostatistics, Mayo Clinic, Jacksonville, FL, 32224, USA.
7
Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.
8
Department of Neurosciences, University of California at San Diego, La Jolla, CA, 92093, USA.
9
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
10
Institute for Metabolic Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany.
11
Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
12
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, 92093, USA.
13
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA. petrucelli.leonard@mayo.edu.
14
Department of Neurology, Mayo Clinic, Jacksonville, FL, 32224, USA. Boylan.Kevin@mayo.edu.

Abstract

Clinical and neuropathological characteristics associated with G4C2 repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, are highly variable. To gain insight on the molecular basis for the heterogeneity among C9ORF72 mutation carriers, we evaluated associations between features of disease and levels of two abundantly expressed "c9RAN proteins" produced by repeat-associated non-ATG (RAN) translation of the expanded repeat. For these studies, we took a departure from traditional immunohistochemical approaches and instead employed immunoassays to quantitatively measure poly(GP) and poly(GA) levels in cerebellum, frontal cortex, motor cortex, and/or hippocampus from 55 C9ORF72 mutation carriers [12 patients with ALS, 24 with frontotemporal lobar degeneration (FTLD) and 19 with FTLD with motor neuron disease (FTLD-MND)]. We additionally investigated associations between levels of poly(GP) or poly(GA) and cognitive impairment in 15 C9ORF72 ALS patients for whom neuropsychological data were available. Among the neuroanatomical regions investigated, poly(GP) levels were highest in the cerebellum. In this same region, associations between poly(GP) and both neuropathological and clinical features were detected. Specifically, cerebellar poly(GP) levels were significantly lower in patients with ALS compared to patients with FTLD or FTLD-MND. Furthermore, cerebellar poly(GP) associated with cognitive score in our cohort of 15 patients. In the cerebellum, poly(GA) levels similarly trended lower in the ALS subgroup compared to FTLD or FTLD-MND subgroups, but no association between cerebellar poly(GA) and cognitive score was detected. Both cerebellar poly(GP) and poly(GA) associated with C9ORF72 variant 3 mRNA expression, but not variant 1 expression, repeat size, disease onset, or survival after onset. Overall, these data indicate that cerebellar abnormalities, as evidenced by poly(GP) accumulation, associate with neuropathological and clinical phenotypes, in particular cognitive impairment, of C9ORF72 mutation carriers.

KEYWORDS:

Amyotrophic lateral sclerosis; C9ORF72 repeat expansion; Cognition; Dipeptide repeat proteins; Frontotemporal dementia; Frontotemporal lobar degeneration; Neuropathological diagnosis; Repeat-associated non-ATG translation; c9RAN proteins

PMID:
26350237
PMCID:
PMC4575385
DOI:
10.1007/s00401-015-1474-4
[Indexed for MEDLINE]
Free PMC Article

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