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Related Experiment Video

Updated: Oct 5, 2025

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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
PubMed
Summary
This summary is machine-generated.

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.

Keywords:
C9orf72HDAC6amyotrophic lateral sclerosisdipeptide repeat proteinsfrontotemporal dementia

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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.