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TFEB-mediated autophagy rescues midbrain dopamine neurons from ?-synuclein toxicity.

ABSTRACT: The aggregation of ?-synuclein plays a major role in Parkinson disease (PD) pathogenesis. Recent evidence suggests that defects in the autophagy-mediated clearance of ?-synuclein contribute to the progressive loss of nigral dopamine neurons. Using an in vivo model of ?-synuclein toxicity, we show that the PD-like neurodegenerative changes induced by excess cellular levels of ?-synuclein in nigral dopamine neurons are closely linked to a progressive decline in markers of lysosome function, accompanied by cytoplasmic retention of transcription factor EB (TFEB), a major transcriptional regulator of the autophagy-lysosome pathway. The changes in lysosomal function, observed in the rat model as well as in human PD midbrain, were reversed by overexpression of TFEB, which afforded robust neuroprotection via the clearance of ?-synuclein oligomers, and were aggravated by microRNA-128-mediated repression of TFEB in both A9 and A10 dopamine neurons. Delayed activation of TFEB function through inhibition of mammalian target of rapamycin blocked ?-synuclein induced neurodegeneration and further disease progression. The results provide a mechanistic link between ?-synuclein toxicity and impaired TFEB function, and highlight TFEB as a key player in the induction of ?-synuclein-induced toxicity and PD pathogenesis, thus identifying TFEB as a promising target for therapies aimed at neuroprotection and disease modification in PD.

SUBMITTER: Decressac M

PROVIDER: S-EPMC3651458 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity.

Decressac Mickael M Mattsson Bengt B Weikop Pia P Lundblad Martin M Jakobsson Johan J Björklund Anders A

Proceedings of the National Academy of Sciences of the United States of America 20130422 19

The aggregation of α-synuclein plays a major role in Parkinson disease (PD) pathogenesis. Recent evidence suggests that defects in the autophagy-mediated clearance of α-synuclein contribute to the progressive loss of nigral dopamine neurons. Using an in vivo model of α-synuclein toxicity, we show that the PD-like neurodegenerative changes induced by excess cellular levels of α-synuclein in nigral dopamine neurons are closely linked to a progressive decline in markers of lysosome function, accomp ...[more]

PMID: 23610405

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Project description:BackgroundThe mechanisms through which aberrant alpha-synuclein (ASYN) leads to neuronal death in Parkinson's disease (PD) are uncertain. In isolated liver lysosomes, mutant ASYNs impair Chaperone Mediated Autophagy (CMA), a targeted lysosomal degradation pathway; however, whether this occurs in a cellular context, and whether it mediates ASYN toxicity, is unknown. We have investigated presently the effects of WT or mutant ASYN on the lysosomal pathways of CMA and macroautophagy in neuronal cells and assessed their impact on ASYN-mediated toxicity.Methods and findingsNovel inducible SH-SY5Y and PC12 cell lines expressing human WT and A53T ASYN, as well as two mutant forms that lack the CMA-targeting motif were generated. Such forms were also expressed in primary cortical neurons, using adenoviral transduction. In each case, effects on long-lived protein degradation, LC3 II levels (as a macroautophagy index), and cell death and survival were assessed. In both PC12 and SH-SY5Y cycling cells, induction of A53T ASYN evoked a significant decrease in lysosomal degradation, largely due to CMA impairment. In neuronally differentiated SH-SH5Y cells, both WT and A53T ASYN induction resulted in gradual toxicity, which was partly dependent on CMA impairment and compensatory macroautophagy induction. In primary neurons both WT and A53T ASYN were toxic, but only in the case of A53T ASYN did CMA dysfunction and compensatory macroautophagy induction occur and participate in death.ConclusionsExpression of mutant A53T, and, in some cases, WT ASYN in neuronal cells leads to CMA dysfunction, and this in turn leads to compensatory induction of macroautophagy. Inhibition of these lysosomal effects mitigates ASYN toxicity. Therefore, CMA dysfunction mediates aberrant ASYN toxicity, and may be a target for therapeutic intervention in PD and related disorders. Furthermore, macroautophagy induction in the context of ASYN over-expression, in contrast to other settings, appears to be a detrimental response, leading to neuronal death.

Dataset Information

TFEB-mediated autophagy rescues midbrain dopamine neurons from ?-synuclein toxicity.

Publications

TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity.

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