title: TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity.
abstract: 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.
authors.affiliation: Department of Experimental Medical Sciences, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden. Mickael.Decressac@med.lu.se
authors.forename: Mickael
authors.initials: M
authors.lastname: Decressac
authors.forename: Bengt
authors.initials: B
authors.lastname: Mattsson
authors.forename: Pia
authors.initials: P
authors.lastname: Weikop
authors.forename: Martin
authors.initials: M
authors.lastname: Lundblad
authors.forename: Johan
authors.initials: J
authors.lastname: Jakobsson
authors.forename: Anders
authors.initials: A
authors.lastname: Björklund
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism / Q000502:physiology*; D000071186:Beclin-1; D001921:Brain / Q000378:metabolism; D001931:Brain Mapping / Q000379:methods; D000229:Dependovirus; D004298:Dopamine; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D008247:Lysosomes / Q000378:metabolism; D008636:Mesencephalon / Q000473:pathology*; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D018696:Neuroprotective Agents; C064972:TFEB protein, human; C574124:TFEB protein, rat; D051844:alpha-Synuclein; D004298:Dopamine
keywords: Beclin; adeno-associated virus; aggregates; synucleinopathy