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HDAC6 Interacts With Poly (GA) and Modulates its Accumulation in c9FTD/ALS
Giulia Del Rosso1,2, Yari Carlomagno1, Tiffany W Todd1
1Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States.
Frontiers in Cell and Developmental Biology
|January 31, 2022
Summary
HDAC6 interacts with toxic poly (GA) proteins in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Reducing HDAC6 levels decreased toxic protein inclusions in a mouse model, suggesting HDAC6 as a therapeutic target for C9orf72-related FTD/ALS.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- C9orf72 repeat expansions are the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).
- Aberrant translation produces toxic dipeptide repeat (DPR) proteins, including poly (GA), which accumulate in the central nervous system.
Purpose of the Study:
- To investigate the role of HDAC6 in the pathology of C9orf72-related FTD/ALS.
- To determine if targeting HDAC6 could be a therapeutic strategy.
Main Methods:
- Immunoprecipitation and co-localization studies to assess HDAC6-poly (GA) interaction in patient tissues and a mouse model.
- Cellular assays to evaluate the effect of HDAC6 overexpression on poly (GA) levels.
- Stereotaxic injection of antisense oligonucleotides to reduce HDAC6 expression in c9FTD/ALS mice.
Main Results:
- HDAC6 specifically interacts with and co-localizes with poly (GA) inclusions in patient samples and a c9FTD/ALS mouse model.
- HDAC6 overexpression increases poly (GA) levels independently of its deacetylase activity.
- Reducing HDAC6 expression significantly decreases poly (GA) inclusions in the mouse model.
Conclusions:
- HDAC6 plays a critical role in modulating poly (GA) pathology through a physical interaction mechanism.
- Pharmacological reduction of HDAC6 levels represents a potential therapeutic approach for C9orf72-related FTD and ALS.
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