HDAC6 regulates mutant SOD1 aggregation through two SMIR motifs and tubulin acetylation

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Familial amyotrophic lateral sclerosis (ALS) is linked to mutations in Cu/Zn superoxide dismutase (SOD1), leading to protein aggregation.
• The specific role of histone deacetylase 6 (HDAC6) in mutant SOD1 aggregation and ALS pathogenesis remains largely unknown.

Purpose of the Study:

• To investigate the role of HDAC6 in the aggregation of mutant SOD1.
• To elucidate the molecular mechanisms by which HDAC6 influences mutant SOD1 aggregation and ALS pathology.

Main Methods:

• HDAC6 knockdown in cultured cells expressing mutant SOD1.
• Analysis of HDAC6-mutant SOD1 interactions using identified motifs (SMIR).
• Assessment of α-tubulin acetylation levels and its impact on mutant SOD1 aggregation.

Main Results:

• HDAC6 knockdown significantly increased mutant SOD1 aggregation.
• HDAC6 selectively interacted with mutant SOD1 through SMIR-like motifs.
• Mutant SOD1 expression elevated α-tubulin acetylation, and acetylation-mimicking mutants exacerbated SOD1 aggregation.

Conclusions:

• Mutant SOD1 modulates HDAC6 activity, increasing tubulin acetylation.
• Elevated tubulin acetylation promotes microtubule- and retrograde transport-dependent mutant SOD1 aggregation.
• HDAC6 impairment may be a shared characteristic across various ALS subtypes.