Neuroprotection by Epigenetic Modulation in a Transgenic Model of Multiple System Atrophy.
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.
Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Anichstr. 35, 6020, Innsbruck, Austria.
Edith
E
Sturm
Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Anichstr. 35, 6020, Innsbruck, Austria.
Lisa
L
Fellner
Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Anichstr. 35, 6020, Innsbruck, Austria.
Florian
F
Krismer
Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Anichstr. 35, 6020, Innsbruck, Austria.
Werner
W
Poewe
Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Anichstr. 35, 6020, Innsbruck, Austria.
Gregor K
GK
Wenning
Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Anichstr. 35, 6020, Innsbruck, Austria. nadia.stefanova@i-med.ac.at.
Nadia
N
Stefanova
D000375:Aging / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D020233:Gait Disorders, Neurologic / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019578:Multiple System Atrophy / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018991:Myelin Proteolipid Protein / Q000235:genetics; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010654:Phenylbutyrates / Q000494:pharmacology* / Q000627:therapeutic use*; D011401:Promoter Regions, Genetic / Q000235:genetics; D000071617:Protein Deglycase DJ-1 / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
D018991:Myelin Proteolipid Protein; D018696:Neuroprotective Agents; D010654:Phenylbutyrates; C047516:Plp1 protein, mouse; D051844:alpha-Synuclein; C075773:4-phenylbutyric acid; D000071617:Protein Deglycase DJ-1
histone acetylation; neuroprotection; nigral degeneration; phenylbutyrate; α-Synuclein