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

Decressac, MickaelLund University,Lunds universitet,Neurobiologi,Forskargrupper vid Lunds universitet,Neurobiology,Lund University Research Groups (författare)

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.

Mattsson, BengtLund University,Lunds universitet,Neurobiologi,Forskargrupper vid Lunds universitet,Neurobiology,Lund University Research Groups(Swepub:lu)neur-bma (författare)
Weikop, Pia (författare)
Lundblad, MartinLund University,Lunds universitet,Neurobiologi,Forskargrupper vid Lunds universitet,Neurobiology,Lund University Research Groups(Swepub:lu)mphy-mlu (författare)
Jakobsson, JohanLund University,Lunds universitet,Molekylär neurogenetik,Forskargrupper vid Lunds universitet,Neurobiologi,Molecular Neurogenetics,Lund University Research Groups,Neurobiology(Swepub:lu)mphy-jja (författare)
Björklund, AndersLund University,Lunds universitet,Neurobiologi,Forskargrupper vid Lunds universitet,Neurobiology,Lund University Research Groups(Swepub:lu)mphy-abj (författare)
NeurobiologiForskargrupper vid Lunds universitet (creator_code:org_t)

Ingår i:Proceedings of the National Academy of Sciences: Proceedings of the National Academy of Sciences110:19, s. 1817-18261091-64900027-8424

Av författaren/redakt...: Decressac, Micka ...; Mattsson, Bengt; Weikop, Pia; Lundblad, Martin; Jakobsson, Johan; Björklund, Ander ...

Om ämnet

MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Medicinska och f ...; och Neurovetenskaper

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.