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Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations
Ian R Mackenzie1, Thomas Arzberger, Elisabeth Kremmer
1Department of Pathology, Vancouver General Hospital, University of British Columbia, Vancouver, Canada.
Acta Neuropathologica
|October 8, 2013
Summary
Hexanucleotide repeat expansions in C9ORF72 cause frontotemporal dementia and motor neuron disease. Dipeptide repeat (DPR) protein pathology is widespread but doesn't correlate with neurodegeneration, suggesting TDP-43 accumulation drives disease progression.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- C9ORF72 gene expansions are the leading genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).
- Unconventional translation produces dipeptide repeat (DPR) proteins (poly-GA, -GR, -GP) and TDP-43 pathology in C9ORF72-associated neurodegenerative diseases.
Purpose of the Study:
- To characterize novel antibodies against poly-GA and analyze the neuroanatomical distribution of DPR and TDP-43 pathology in C9ORF72 mutation carriers.
- To investigate the relationship between DPR and TDP-43 pathology and clinical phenotypes and neurodegeneration.
Main Methods:
- Developed and utilized novel monoclonal antibodies targeting poly-GA.
- Examined brain tissue from 35 C9ORF72 mutation cases with diverse clinical presentations.
- Assessed the neuroanatomical distribution and load of DPR and TDP-43 pathology and correlated findings with clinical data and neurodegeneration severity.
Main Results:
- DPR pathology distribution was consistent across cases, with high loads in the cerebellum, neocortex, and hippocampus, regardless of clinical phenotype.
- No correlation was found between the extent of DPR pathology and the degree of neurodegeneration.
- TDP-43 pathology showed a strong association with clinical phenotype and regional neurodegeneration.
Conclusions:
- DPR pathology is a direct consequence of C9ORF72 mutations.
- The dissociation between DPR load and neurodegeneration suggests DPR inclusions may be a protective mechanism.
- TDP-43 accumulation and associated downstream effects are likely key drivers of neurodegeneration in C9ORF72 disease.
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