Abstract
Similar to Parkinson disease, multiple system atrophy (MSA) presents neuropathologically with nigral neuronal loss; however, the hallmark intracellular α-synuclein (αSyn) accumulation in MSA affects typically oligodendrocytes to form glial cytoplasmic inclusions. The underlying pathogenic mechanisms remain unclear. As MSA is predominantly sporadic, epigenetic mechanisms may play a role. We tested the effects of the pan-histone deacetylase inhibitor (HDACi) sodium phenylbutyrate in aged mice overexpressing αSyn under the control of the proteolipid protein promoter (PLP–αSyn) designed to model MSA and characterized by αSyn accumulation in oligodendrocytes and nigral neurodegeneration. HDACi improved motor behavior and survival of nigral neurons in PLP–αSyn mice. Furthermore, HDACi reduced the density of oligodendroglial αSyn aggregates, which correlated with the survival of nigral neurons in PLP–αSyn mice. For the first time, we suggest a role of HDACi in the pathogenesis of MSA-like neurodegeneration and support the future development of selective HDACi for MSA therapy.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-016-0447-1) contains supplementary material, which is available to authorized users.
Highlights
Histone acetylation has been implicated in the pathogenesis of various neurodegenerative diseases [1,2,3]
We found significantly shortened stride length in aged proteolipid protein (PLP)–αSyn transgenic mice compared with age, sex, and backgroundmatched nontransgenic control mice when recorded at 25 cm/s in the DigiGait system, confirming previous data [12]
The current study provides, for the first time, evidence on the beneficial effects of HDAC inhibitor (HDACi) in aged PLP–αSyn mice
Summary
Histone acetylation has been implicated in the pathogenesis of various neurodegenerative diseases [1,2,3]. We hypothesize that αSyn in MSA may interfere with histone acetylation in glial and neuronal cells and that this may play a role in the disease process, representing a new potential therapeutic target. To test this hypothesis, we sought to analyze the effects of sodium phenylbutyrate (NaPB), a nonselective pan-HDAC inhibitor (HDACi) in a transgenic mouse model of MSA, based on targeted overexpression of full-length human αSyn under the proteolipid protein (PLP) promoter in oligodendrocytes [10]
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