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TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity
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TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity
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TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity
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Journal Article
TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity
2013
Overview
SignificanceThis study shows that neurodegenerative changes induced by α-synuclein in midbrain dopamine neurons in vivo can be blocked through activation of the autophagy-lysosome pathway. Using an adeno-associated virus model of Parkinson disease to overexpress α-synuclein in the substantia nigra, we show that genetic [transcription factor EB (TFEB) and Beclin-1 overexpression] or pharmacological (rapalog) manipulations that enhance autophagy protect nigral neurons from α-synuclein toxicity, but inhibiting autophagy exacerbates α-synuclein toxicity. The results provide a mechanistic link between α-synuclein toxicity and impaired TFEB function, and identify TFEB as a target for therapies aimed at neuroprotection and disease modification in Parkinson disease.
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, 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 α-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 α-synuclein induced neurodegeneration and further disease progression. The results provide a mechanistic link between α-synuclein toxicity and impaired TFEB function, and highlight TFEB as a key player in the induction of α-synuclein–induced toxicity and PD pathogenesis, thus identifying TFEB as a promising target for therapies aimed at neuroprotection and disease modification in PD.
Publisher
National Academy of Sciences
Subject
/ Animals
/ Apoptosis Regulatory Proteins - biosynthesis
/ Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism
/ Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - physiology
/ Beclin-1
/ brain
/ Dopamine
/ Female
/ Humans
/ Medicinska och farmaceutiska grundvetenskaper
/ neurons
/ Neuroprotective Agents - pharmacology
/ Parkinson Disease - metabolism
/ Parkinson Disease - pathology
/ PNAS PLUS: SIGNIFICANCE STATEMENTS
/ Rats
/ toxicity
