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HDAC6 inhibitors: Translating genetic and molecular insights into a therapy for axonal CMT
Elisabeth Rossaert1, Ludo Van Den Bosch1
1KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), Leuven, Belgium; VIB - Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium.
Abstract:
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.
Insights
Histone deacetylase 6 (HDAC6) impacts neuronal survival pathways in Charcot-Marie-Tooth disease (CMT). Targeting HDAC6 with inhibitors shows promise for treating axonal CMT by improving axonal transport and regeneration.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Histone deacetylase 6 (HDAC6) is crucial for neuronal survival.
- Charcot-Marie-Tooth disease (CMT) encompasses various axonal forms impacting neuronal health.
- HDAC6's role in axonal CMT pathogenesis is under investigation.
Purpose of the Study:
- To review evidence linking HDAC6 to axonal CMT disease pathways.
- To explore HDAC6's dual role in axonal transport, regeneration, and protein degradation.
- To evaluate HDAC6 inhibition as a therapeutic strategy for axonal CMT.
Main Methods:
- Literature review of current evidence on HDAC6 and axonal CMT.
- Analysis of HDAC6's deacetylase-dependent and -independent functions.
- Examination of preclinical studies on HDAC6 inhibitors in CMT models.
Main Results:
- HDAC6 negatively affects axonal transport and regeneration in an activity-dependent manner.
- HDAC6 mediates protective responses against misfolded proteins, largely independent of its deacetylase activity.
- Preclinical studies show beneficial effects of HDAC6 inhibitors in axonal CMT models.
Conclusions:
- HDAC6 actively contributes to the pathogenesis of certain axonal CMT forms.
- Targeting HDAC6's deacetylase activity is a promising therapeutic avenue.
- Small-molecule HDAC6 inhibitors offer a potential treatment strategy for axonal CMT.
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