期刊
JOURNAL OF NEUROCHEMISTRY
卷 135, 期 1, 页码 194-205出版社
WILEY
DOI: 10.1111/jnc.13256
关键词
3-NP; CCCP; glial cytoplasmic inclusions; multiple system atrophy; oligodendrocytes; ubiquitin-proteasome system
资金
- Deutsche Forschungsgemeinschaft [RI 384/16-2]
alpha-Synuclein (alpha-syn)-containing glial cytoplasmic inclusions originating in oligodendrocytes are characteristically observed in multiple system atrophy. The mechanisms of glial cytoplasmic inclusion formation remain rather elusive. alpha-Syn overexpression, uptake from the environment, oxidative stress or impairment of the proteolytic degradation systems have been discussed. Here, we investigated whether in oligodendrocytes autophagy plays a major role in the degradation and aggregation of endogenously expressed alpha-syn and of alpha-syn taken up from the extracellular environment. Furthermore, we studied whether in cells with impaired mitochondria the accumulation and aggregation of exogenously added alpha-syn is promoted. Using primary cultures of rat brain oligodendrocytes and an oligodendroglial cell line, genetically engineered to express green fluorescent protein-microtubule-associated light chain 3 with or without alpha-syn to monitor the autophagic flux, we demonstrate that both exogenously applied alpha-syn and alpha-syn stably expressed endogenously are effectively degraded by autophagy and do not affect the autophagic flux per se. Mitochondrial impairment with the protonophore carbonyl cyanide 3-chlorophenylhydrazone or 3-nitropropionic acid disturbs the autophagic pathway and leads to the accumulation of exogenously applied alpha-syn and enhances its propensity to form aggregates intracellularly. Thus, mitochondrial dysfunction and oxidative stress, which occur over time and are significant pathological features in synucleinopathies, have an impact on the autophagic pathway and participate in pathogenesis.
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