Neuroprotection by Epigenetic Modulation in a Transgenic Model of Multiple System Atrophy.

ABSTRACT: Similar to Parkinson disease, multiple system atrophy (MSA) presents neuropathologically with nigral neuronal loss; however, the hallmark intracellular ?-synuclein (?Syn) 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 ?Syn under the control of the proteolipid protein promoter (PLP-?Syn) designed to model MSA and characterized by ?Syn accumulation in oligodendrocytes and nigral neurodegeneration. HDACi improved motor behavior and survival of nigral neurons in PLP-?Syn mice. Furthermore, HDACi reduced the density of oligodendroglial ?Syn aggregates, which correlated with the survival of nigral neurons in PLP-?Syn 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.

SUBMITTER: Sturm E 

PROVIDER: S-EPMC5081120 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature