Journal Article

DZNE-2020-03154

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS.

Mori, K. ; Weng, S.-M.DZNE* ; Arzberger, T. ; May, S.DZNE* ; Rentzsch, K.DZNE* ; Kremmer, E. ; Schmid, B.DZNE* ; Kretzschmar, H. A. ; Cruts, M. ; Van Broeckhoven, C. ; Haass, C.DZNE* ; Edbauer, D. (Last author)DZNE*

2013
Assoc.60841 Washington, DC

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Please use a persistent id in citations: doi:10.1126/science.1232927

Abstract: Expansion of a GGGGCC hexanucleotide repeat upstream of the C9orf72 coding region is the most common cause of familial frontotemporal lobar degeneration and amyotrophic lateral sclerosis (FTLD/ALS), but the pathomechanisms involved are unknown. As in other FTLD/ALS variants, characteristic intracellular inclusions of misfolded proteins define C9orf72 pathology, but the core proteins of the majority of inclusions are still unknown. Here, we found that most of these characteristic inclusions contain poly-(Gly-Ala) and, to a lesser extent, poly-(Gly-Pro) and poly-(Gly-Arg) dipeptide-repeat proteins presumably generated by non-ATG-initiated translation from the expanded GGGGCC repeat in three reading frames. These findings directly link the FTLD/ALS-associated genetic mutation to the predominant pathology in patients with C9orf72 hexanucleotide expansion.

Keyword(s): Adaptor Proteins, Signal Transducing: metabolism (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; C9orf72 Protein (MeSH) ; Cerebellum: metabolism (MeSH) ; Cerebellum: pathology (MeSH) ; DNA Repeat Expansion (MeSH) ; DNA-Binding Proteins: metabolism (MeSH) ; Frontotemporal Lobar Degeneration: genetics (MeSH) ; Frontotemporal Lobar Degeneration: metabolism (MeSH) ; Frontotemporal Lobar Degeneration: pathology (MeSH) ; Heterozygote (MeSH) ; Hippocampus: metabolism (MeSH) ; Hippocampus: pathology (MeSH) ; Humans (MeSH) ; Open Reading Frames (MeSH) ; Protein Biosynthesis (MeSH) ; Proteins: genetics (MeSH) ; Proteins: metabolism (MeSH) ; Sequestosome-1 Protein (MeSH) ; Adaptor Proteins, Signal Transducing ; C9orf72 Protein ; C9orf72 protein, human ; DNA-Binding Proteins ; Proteins ; SQSTM1 protein, human ; Sequestosome-1 Protein

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Contributing Institute(s):

1. ALS, FTLD and Zebrafish models (AG Haass old)
2. Cell Biology of Neurodegeneration (AG Edbauer)
3. Zebrafish Models (Zebrafish Models ; AG Schmid ; AG Schmid München)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2013

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; IF >= 40 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

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