title: An amyloid-like cascade hypothesis for C9orf72 ALS/FTD.
abstract: Expansion of a GGGGCC repeat in C9orf72 causes amyotrophic lateral sclerosis, frontotemporal dementia, or a combination of both. Bidirectional repeat transcripts sequester RNA-binding proteins into nuclear RNA foci. The repeat is translated into dipeptide repeat (DPR) proteins that are crucial for repeat-induced toxicity. DPRs inhibit the proteasome and sequester other proteins. These changes are accompanied by widespread brain atrophy and subclinical cognitive impairment before disease onset. Both repeat RNA and DPRs impair nucleocytoplasmic transport and promote TDP-43 mislocalization and aggregation. Thus, repeat RNA and DPRs may gradually trigger TDP-43 pathology and subsequent region-specific neurodegeneration in a cascade similar to amyloid-β peptide in Alzheimer's disease. The key components of the C9orf72 cascade are promising therapeutic targets in different disease stages.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Feodor-Lynen-Str. 17, 81377 Munich, Germany; Munich Cluster of Systems Neurology (SyNergy), Feodor-Lynen-Str. 17, 81377 Munich, Germany; Ludwig-Maximilians University Munich, 81377 Munich, Germany. Electronic address: dieter.edbauer@dzne.de.
authors.forename: Dieter
authors.initials: D
authors.lastname: Edbauer
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Feodor-Lynen-Str. 17, 81377 Munich, Germany; Munich Cluster of Systems Neurology (SyNergy), Feodor-Lynen-Str. 17, 81377 Munich, Germany; Biomedical Center (BMC), Ludwig-Maximilians University Munich, Feodor-Lynen-Str. 17, 81377 Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001284:Atrophy; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D000073885:C9orf72 Protein; D003072:Cognition Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D042622:DNA Repeat Expansion / Q000235:genetics; D004151:Dipeptides / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D066263:Protein Aggregation, Pathological / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000378:metabolism; D057177:TDP-43 Proteinopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004151:Dipeptides; D011506:Proteins; D016601:RNA-Binding Proteins