Journal
BRAIN RESEARCH
Volume 1733, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.brainres.2020.146692
Keywords
Charcot-Marie-Tooth disease; CMT2; Axonal transport; Axonal regeneration; Protein aggregation; HDAC6 inhibitors
Categories
Funding
- VIB
- KU Leuven
- Fund for Scientific Research Flanders (FWO-Vlaanderen)
- Thierry Latran Foundation
- Association Belge contre les Maladies neuro-Musculaires -aide a la recherche ASBL (ABMM)
- Muscular Dystrophy Association (MDA)
- ALS Liga Belgie (A Cure for ALS)
- ALS Association (ALSA)
- Agency for Innovation by Science and Technology in Flanders
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Histone deacetylase 6 (HDAC6) plays a central role in various processes that are key for neuronal survival. In this review, we summarize the current evidence related to disease pathways in the axonal form of Charcot-Marie-Tooth disease (CMT) and highlight the role of HDAC6 in these pathways. We hypothesize that HDAC6 might in fact actively contribute to the pathogenesis of certain forms of axonal CMT. HDAC6 plays a deacetylase activity-dependent, negative role in axonal transport and axonal regeneration, which are both processes implicated in axonal CMT. On the other hand, HDAC6 coordinates a protective response during elimination of toxic misfolded proteins, but this is mostly mediated independent of its deacetylase activity. The current mechanistic insights on these functions of HDAC6 in axonal CMT, along with the selective druggability against its deacetylase activity, make the targeting of HDAC6 particularly attractive. We elaborate on the preclinical studies that demonstrated beneficial effects of HDAC6 inhibitors in axonal CMT models and outline possible modes of action. Overall, this overview ultimately provides a rationale for the use of small-molecule HDAC6 inhibitors as a therapeutic strategy for this devastating disease.
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