HDAC6 as a potential therapeutic target for peripheral nerve disorders

ABSTRACT

Introduction: Peripheral neuropathies are a heterogeneous group of diseases that are characterized by a progressive, ascending loss of nerve function arising from the peripheral regions of the limbs. The phenotypic overlap between different types of hereditary and acquired peripheral neuropathies indicates that similar pathophysiological processes are at play. Many downstream pathways in peripheral neurons, such as axonal transport, protein degradation, and interactions with Schwann cells, organelle damage, channelopathies, and neuroinflammatory signaling, have been proposed and each affects peripheral nerves in a negative way. Histone deacetylase 6 (HDAC6) plays an important role at the intersection of these converging pathogenic pathways. The enzymatic deacetylase activity of HDAC6 is upregulated in neurodegenerative disorders and typically results in downstream neuronal stress.

Areas covered: The role of HDAC6 in the common pathogenic mechanisms of peripheral neuropathies. In addition, we discuss the current preclinical and clinical HDAC6 inhibitors (HDAC6i), their chemical structure, development, and limitations.

Expert opinion: The development and testing of non-hydroxamic acid-based, should be the focus of the future research. Moreover, HDAC6i should be further investigated as a preventative measure and therapeutic strategy for inherited and acquired peripheral neuropathies.

KEYWORDS:

• HDAC6
• acquired neuropathies
• peripheral neuropathies
• Charcot-Marie-Tooth disease
• axonal transport
• axonal degeneration
• demyelination
• hydroxamic acid

Article Highlights

• Peripheral neuropathies have common underlying pathogenic mechanisms.

• HDAC6 plays a role in several neurodegenerative pathways.

• HDAC6 inhibitors offer a valid therapeutic strategy for peripheral neuropathies.

• The most potent HDAC6 inhibitors have a hydroxamic acid-based structure, which could render them unsuitable for long-term treatments.

• Non-hydroxamate HDAC6 inhibitors are a more clinically favorable approach.

This box summarizes key points contained in the article.

Declaration of interest

R. Prior and Y.E. Klingl are Strategic Basic (SB) PhD fellows at Fund for Scientific Research Flanders, Research Foundation–Flanders (FWO-Vlaanderen), project numbers 1S59317N and 1S50318N, respectively. R. Prior was also supported by the National University of Ireland, Travelling Studentship. L. Van Helleputte was supported by the ‘Agency for Innovation by Science and Technology in Flanders’ (IWT-Vlaanderen). Research of L. Van Den Bosch was supported by VIB, KU Leuven (Internal Funds and ‘Opening the Future’), FWO-Vlaanderen, the Thierry Latran Foundation, the Association Française contre les Myopathies (AFM), the Association Belge contre les Maladies neuro-Musculaires (ABMM), the ALS Liga (Belgium), the Muscular Dystrophy Association (MDA) and the National Institutes of Health [NIH, NS079183]. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.