Exp Neurobiol.  2019 Aug;28(4):504-515. 10.5607/en.2019.28.4.504.

HDAC Inhibition by Valproic Acid Induces Neuroprotection and Improvement of PD-like Behaviors in LRRK2 R1441G Transgenic Mice

• Kim T
• Song S
• Park Y
• Kang S
• Seo H

• KMID: 2458548
• DOI: http://doi.org/10.5607/en.2019.28.4.504

Abstract

Parkinson's disease (PD) is one of the late-onset neurodegenerative movement disorder. Major pathological markers of PD include progressive loss of dopaminergic neurons, Lewy body formation, genetic mutations, and environmental factors. Epigenetic regulation of specific gene expression via impaired histone acetylation is associated with neuronal dysfunction in various neurodegenerative diseases. In this study, we hypothesized that histone deacetylase (HDAC) inhibitor, valproic acid (VPA), can improve motor function by enhancing cell survival in PD genetic model mice with LRRK2 R1441G mutation. To address this question, we administered VPA in LRRK2 R1441G transgenic mice to determine whether VPA affects 1) histone acetylation and HDAC expression, 2) dopaminergic neuron survival, 3) inflammatory responses, 4) motor or non-motor symptoms. As results, VPA administration increased histone acetylation level and the number of tyrosine hydroxylase (TH) positive neurons in substantia nigra of LRRK2 R1441G mice. VPA reduced iba-1 positive activated microglia and the mRNA levels of pro-inflammatory marker genes in LRRK2 R1441G mice. In addition, VPA induced the improvement of PD-like motor and non-motor behavior in LRRK2 R1441G mice. These data suggest that the inhibition of HDAC can be further studied as potential future therapeutics for PD.

Keyword

Parkinson’s disease (PD); Histone deacetylase (HDAC); Valproic acid (VPA); Neuroprotection

MeSH Terms

Acetylation
Animals
Cell Survival
Dopaminergic Neurons
Epigenomics
Gene Expression
Histone Deacetylases
Histones
Lewy Bodies
Mice
Mice, Transgenic*
Microglia
Models, Genetic
Movement Disorders
Neurodegenerative Diseases
Neurons
Neuroprotection*
RNA, Messenger
Substantia Nigra
Tyrosine 3-Monooxygenase
Valproic Acid*
Histone Deacetylases
Histones
RNA, Messenger
Tyrosine 3-Monooxygenase
Valproic Acid