C9ORF72-ALS/FTD-associated poly(GR) binds Atp5a1 and compromises mitochondrial function in vivo

Topic: Brain proteins, microglia and lab models

The GGGGCC repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, it is not known which dysregulated molecular pathways are primarily responsible for disease initiation or progression. We established an inducible mouse model of poly(GR) toxicity in which (GR) 80 gradually accumulates in cortical excitatory neurons. Low-level poly(GR) expression induced FTD/ALS-associated synaptic dysfunction and behavioral abnormalities, as well as age-dependent neuronal cell loss, microgliosis and DNA damage, probably caused in part by early defects in mitochondrial function. Poly(GR) bound preferentially to the mitochondrial complex V component ATP5A1 and enhanced its ubiquitination and degradation, consistent with reduced ATP5A1 protein level in both (GR) 80 mouse neurons and patient brains. Moreover, inducing ectopic Atp5a1 expression in poly(GR)-expressing neurons or reducing poly(GR) level in adult mice after disease onset rescued poly(GR)-induced neurotoxicity. Thus, poly(GR)-induced mitochondrial defects are a major driver of disease initiation in C9ORF72-related ALS/FTD.

@article{choi2019-31086314,
  author  = {Choi, S. Y. and Lopez-Gonzalez, R. and Krishnan, G. and Phillips, H. L. and Li, A. N. and Seeley, W. W. and Yao, W. D. and Almeida, S. and others},
  title   = {{C9ORF72-ALS/FTD-associated poly(GR) binds Atp5a1 and compromises mitochondrial function in vivo}},
  journal = {Nature neuroscience},
  year    = {2019},
  doi     = {10.1038/s41593-019-0397-0},
  pmid    = {31086314},
  url     = {https://doi.org/10.1038/s41593-019-0397-0}
}

Key findings

• We established an inducible mouse model of poly(GR) toxicity in which (GR) 80 gradually accumulates in cortical excitatory neurons.
• Low-level poly(GR) expression induced FTD/ALS-associated synaptic dysfunction and behavioral abnormalities, as well as age-dependent neuronal cell loss, microgliosis and DNA damage, probably caused in part by early defects in mitochondrial function.
• Poly(GR) bound preferentially to the mitochondrial complex V component ATP5A1 and enhanced its ubiquitination and degradation, consistent with reduced ATP5A1 protein level in both (GR) 80 mouse neurons and patient brains.
• Moreover, inducing ectopic Atp5a1 expression in poly(GR)-expressing neurons or reducing poly(GR) level in adult mice after disease onset rescued poly(GR)-induced neurotoxicity.
• Thus, poly(GR)-induced mitochondrial defects are a major driver of disease initiation in C9ORF72-related ALS/FTD.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/s41593-019-0397-0
• PubMed: 31086314
• Original source →

Free copy unknown: no free-copy check has an answer for this record yet. That does not mean it is paywalled.

Related studies in Disease mechanisms

• Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD - a Systematic Review and Meta-Analysis Cerebellum (London, England) · 2021-09-07 · usefulness score 50/100
• ALS/FTD-Linked Mutation in FUS Suppresses Intra-axonal Protein Synthesis and Drives Disease Without Nuclear Loss-of-Function of FUS Neuron · 2018-10-18 · usefulness score 41/100
• NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer's disease Neuron · 2014-12-18 · usefulness score 36/100
• In vivo tau pathology is associated with synaptic loss and altered synaptic function Alzheimer's research & therapy · 2021-02-05 · usefulness score 47/100
• An N-terminal fragment of the prion protein binds to amyloid-β oligomers and inhibits their neurotoxicity in vivo The Journal of biological chemistry · 2013-01-28 · usefulness score 40/100
• Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS Nature medicine · 2024-06-18 · usefulness score 62/100

Also tagged “tdp-43”

1,150 studies in the library carry the topic tag “tdp-43”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,150 tagged studies.

• Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration Proceedings of the National Academy of Sciences of the United States of America · 2013-10-29 · usefulness score 53/100 · Lewy body dementia
• High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice Journal of neurochemistry · 2008-07-01 · usefulness score 45/100 · Inflammation and the immune system
• Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs Nature neuroscience · 2012-09-30 · usefulness score 56/100 · Lewy body dementia

Similar studies

• Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS 2015 · Lewy body dementia
• G-quadruplex-binding small molecules ameliorate <i>C9orf72</i> FTD/ALS pathology <i>in vitro</i> and <i>in vivo</i> 2018 · Caregiving
• Proteomics and <i>C9orf72</i> neuropathology identify ribosomes as poly-GR/PR interactors driving toxicity 2018 · Clinical safety
• There has been an awakening: Emerging mechanisms of C9orf72 mutations in FTD/ALS 2016 · Clinical safety
• Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs 2016 · Lewy body dementia
• C9orf72-mediated ALS and FTD: multiple pathways to disease 2018 · Lewy body dementia

More on Disease mechanisms

• A review that covers this ground Control of mitochondrial biogenesis and function by the ubiquitin-proteasome system Open biology · 2017-04 · usefulness score 39/100
• Newest in this subject Aβ42 oligomers disrupt calcium homeostasis via Piezo1 and induce neurotoxicity in differentiated SH-SY5Y cells Research Square · 2026-10-29 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject Neuronal Hyperactivity Induces Tau Phosphorylation Selectively in Excitatory Pyramidal Neurons Which Contributes to GluA2 Regulation bioRxiv · 2026-10-28 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in Disease mechanisms →