Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers
Open accessAbstract
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.
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DPR inclusions rarely co-label with TARDBP pathological inclusions and are mainly found in areas of the CNS that are not pathologically affected, arguing against a direct role for DPRs in neurodegeneration.
“On the other hand, DPR inclusions rarely co-label with TARDBP pathological inclusions and are mainly found in areas of the CNS that are not pathologically affected [171,174–177], arguing against a direct role for DPRs in neurodegeneration.”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [175]
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- Authors
- Gendron, T. F., van Blitterswijk, M., Bieniek, K. F., Daughrity, L. M., Jiang, J., Rush, B. K., Pedraza, O., Lucas, J. A., Murray, M. E., Desaro, P., Robertson, A., Overstreet, K., Thomas, C. S., Crook, J. E., Castanedes-Casey, M., Rousseau, L., Josephs, K. A., Parisi, J. E., Knopman, D. S., Petersen, R. C., Boeve, B. F., Graff-Radford, N. R., Rademakers, R., Lagier-Tourenne, C., Edbauer, D., Cleveland, D. W., Dickson, D. W., Petrucelli, L., & Boylan, K. B.
- Affiliations
- Mayo Clinic (US)
- University of California San Diego (US)
- Mayo Clinic in Florida (US)
- German Center for Neurodegenerative Diseases (DE)
- Corresponding author
- Petrucelli, Leonard
- ORCID
- Gendron, Tania F.
- Bieniek, Kevin F.
- Daughrity, Lillian M.
- Jiang, Jie
- Rush, Beth K.
- Pedraza, Otto
- Lucas, John A.
- Murray, Melissa E.
- Desaro, Pamela
- Robertson, Amelia
- Thomas, Colleen S.
- Crook, Julia E.
- Rousseau, Linda
- Josephs, Keith A.
- Parisi, Joseph E.
- Knopman, David S.
- Petersen, Ronald C.
- Boeve, Bradley F.
- Rademakers, Rosa
- Edbauer, Dieter
- Cleveland, Don W.
- Dickson, Dennis W.
- Petrucelli, Leonard
- Venue
- Acta Neuropathologica
- Published
- 2015-09-08
- Volume
- 130
- Issue
- 4
- Pages
- 559-573
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC4575385
- OpenAlex
- W1610732998
- Cited by
- 106
- References
- 43
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 7 · 2023: 7 · 2022: 11 · 2021: 6 · 2020: 15 · 2019: 12 · 2018: 13 · 2017: 13 · 2016: 14 · 2015: 2
- FWCI
- 9.87
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Institute of Neurological Disorders and Stroke (R21NS089979, R21NS084528, R01NS088689, R01NS063964, R01NS077402, P01NS084974, R01NS080882, F32NS087842)
- U.S. Department of Defense (ALSRP AL130125)
- Mayo Foundation for Medical Education and Research
- Amyotrophic Lateral Sclerosis Association (15-IIP-202, Milton Safenowitz Post Doctoral Fellowship)
- Target ALS
- ALS Therapy Alliance
- Ludwig Institute for Cancer Research
- Seventh Framework Programme (FP7/2014-2019 grant 617198)
- Robert Packard Center for ALS
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- C9orf72, G4C2 repeat expansion, repeat-associated non-ATG translation, cerebellum, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, cognitive impairment, disease heterogeneity, neuropathology
- MeSH terms
- C9orf72 Protein, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Cerebellum, Cognition Disorders, Female, Frontal Lobe, Heterozygote, Hippocampus, Humans, Male, Middle Aged, Motor Cortex, Proteins, RNA, Messenger, Protein Biosynthesis, Cohort Studies, Motor Neuron Disease, DNA Repeat Expansion, Frontotemporal Dementia
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