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C9ORF72-ALS/FTD-associated poly(GR) binds Atp5a1 and compromises mitochondrial function in vivo
So Yoen Choi1, Rodrigo Lopez-Gonzalez1, Gopinath Krishnan1
1Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Nature Neuroscience
|May 16, 2019
Summary
The GGGGCC repeat expansion in C9ORF72 causes ALS and FTD. Poly(GR) accumulation in neurons disrupts mitochondrial function, driving neurotoxicity and disease initiation.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- The GGGGCC repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
- The precise molecular pathways driving C9ORF72-related ALS/FTD pathogenesis remain largely unknown.
- Understanding these pathways is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate the role of poly(GR) toxicity in neuronal dysfunction and disease initiation in a C9ORF72 mouse model.
- To identify the specific molecular mechanisms underlying poly(GR)-induced neurotoxicity.
- To explore potential therapeutic interventions targeting mitochondrial defects.
Main Methods:
- Established an inducible mouse model with gradual accumulation of poly(GR) in cortical excitatory neurons.
- Assessed synaptic function, behavior, neuronal loss, microgliosis, and DNA damage.
- Investigated mitochondrial function, specifically focusing on mitochondrial complex V (ATP5A1).
- Utilized genetic manipulation to modulate Atp5a1 expression or poly(GR) levels in vivo.
Main Results:
- Low-level poly(GR) expression induced synaptic dysfunction, behavioral abnormalities, and age-dependent neurodegeneration.
- Poly(GR) preferentially bound to and promoted the degradation of ATP5A1, a key component of mitochondrial complex V.
- Reduced ATP5A1 protein levels were observed in both mouse models and patient brains.
- Restoring Atp5a1 expression or reducing poly(GR) levels rescued poly(GR)-induced neurotoxicity.
Conclusions:
- Poly(GR)-induced mitochondrial defects, particularly involving ATP5A1, are a major driver of disease initiation in C9ORF72-related ALS/FTD.
- Targeting mitochondrial dysfunction presents a promising therapeutic avenue for C9ORF72-related neurodegenerative diseases.
- This study elucidates a critical molecular mechanism linking genetic mutations to neurotoxicity in ALS and FTD.
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