Therapeutic role of HDAC4 inhibition in the treatment of Huntington’s disease

Kelly Flynn

Introduction. Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the Huntingtin (HTT) gene encoding the huntingtin protein. The HTT mutation results in an accumulation of misfolded proteins leading to neuronal dysfunction and cell death.1-4  HD is clinically characterized by a combination of motor disturbances, cognitive impairments primarily affecting executive function, skeletal muscle dysfunction and atrophy, and psychiatric symptoms.1-3,5,8  Mutant huntingtin protein (mHTT) accumulates within brain cells resulting in extensive loss of medium spiny neurons, which causes marked atrophy in the striatum and cerebral cortex, most distinctly in the caudate nucleus.1-3  Histone Deacetylase 4 (HDAC4) is a Class IIa histone deacetylase enzyme that associates with mHTT and has been implicated in the etiology of several neurodegenerative disorders, including HD.6,7  HDAC4 inhibition and reduction in cellular HDAC4 levels present novel strategies for targeting mHTT aggregation.4,9  Methods. Fluorescent microscopy and HDAC4-specific immunoassays were utilized to establish the roles of HDAC4 in autophagy.7  HD mouse models were used to investigate mHTT-induced skeletal muscle atrophy.8  The anti- neurodegenerative activities of microRNAs were established using HDAC4 mRNA assays to evaluate the therapeutic efficacy of manipulating microRNA-22 (miR-22) for the treatment of HD.10  Results. HDAC4  interacts directly with the autophagy activator Microtubule-associated protein 1S (MAP1S), reduces MAP1S stability, suppresses the autophagy flux mediated by MAP1S, and impairs the degradation of mHTT  aggregates. Blocking the association of HDAC4 with MAP1S accelerates autophagy clearance of mHTT.7  HD mouse models exhibited up-regulated HDAC4 transcripts in the tibialis anterior and extensor digitorum longus muscles, decreased twitch and tetanic forces, and loss of motor units as compared to wild-type littermates.8 Overexpression of miR-22 inhibited neurodegeneration in primary striatal and cortical cultures exposed to a mutated human huntingtin fragment.10  Conclusions. Inhibition of HDAC4 enhances the stability of MAP1S, increases autophagy flux, and improves clearance of mHTT aggregates. The results of the HDAC4-MAP1S study provide a mechanism by which therapeutic reduction in HDAC4-associated activity could reduce accumulation of cytoplasmic mHTT aggregates and alleviate neurodegeneration.7  mHTT results in the rapid development of pathological features that lead to skeletal muscle contractile dysfunction. The connection between HDAC4 gene alterations and physiological function in HD-related skeletal muscle atrophy may serve as a therapeutic target in future HD treatments.8  Enhancing miR-22 expression in neurons comprises a rational therapeutic strategy to regulate levels HDAC4 in HD.10

  1. Coppen EM, Roos Current Pharmacological Approaches to Reduce Chorea in Huntington’s Disease. Drugs.  2016;77(1)29-46.  Doi:10.1007/s40265-016-0670-4.
  2. Malek N, Newman Hereditary chorea – what else to consider when the Huntington’s disease genetics test is negative? Acta Neurologica Scandinavica. 2016;135(1):25-33. Doi:10.1111/ane.12609.
  3. Mestre TA, Sampaio Huntington Disease: Linking Pathogenesis to the Development of Experimental Therapeutics. Current Neurology and Neuroscience Reports. 2017;17(2). Doi:10.1007/s11910-017- 0711-8.
  4. Mielcarek M, Landles C, Weiss A, et HDAC4 Reduction: A Novel Therapeutic Strategy to Target Cytoplasmic Huntingtin and Ameliorate Neurodegeneration. PLoS Biology. 2013;11(11). Doi:10.1371/journal.pbio.1001717.
  5. Craufurd D, Macleod R, Frontali M, et Diagnostic genetic testing for Huntington’s disease. Practical Neurology. 2014;15(1):80-84.  Doi:10.1136/practneurol-2013-000790.
  6. Burli R, Luckhurst C, Aziz O, et Design, Synthesis, and Biological Evaluation of Potent and Selective Class IIa Histone Deacetylase (HDAC) Inhibitors as a Potential Therapy for Huntington’s Disease. Journal of Medicinal Chemistry. 2013;56(24):9934-9954. doi:10.1021/jm4011884.
  7. Yue F, Li W, Zou J, et Blocking the association of HDAC4 with MAP1S accelerates autophagy clearance of mutant Huntingtin. Aging. 2015;7(10):839-853. doi:10.18632/aging.100818.
  8. Mielcarek M, Toczek M, Smeets CJLM, et HDAC4-Myogenin Axis As an Important Marker of HD- Related Skeletal Muscle Atrophy. PLOS Genetics. 2015;11(3). doi:10.1371/journal.pgen.1005021.
  9. Wild EJ, Tabrizi Targets for future clinical trials in Huntington’s disease: What’s in the pipeline? Movement  Disorders.  2014;29(11):1434-1445.  Doi:10.1002/mds.26007.