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-synucleininduced toxicity and PD pathogenesis, thus identifying TFEB as a promising target for therapies aimed at neuroprotection and disease modification in PD.adeno-associated virus | Beclin | aggregates | synucleinopathy A major hallmark of Parkinson disease (PD) that contributes to the progressive loss of nigral dopamine (DA) neurons is α-synucleinopathy. Defects in clearance of oligomeric or misfolded proteins have been associated with aging and several neurodegenerative disorders (1-4). In human PD and related Lewy Body diseases, the presence of α-synuclein-positive (α-syn + ) aggregates is associated with accumulation of autophagosomes and reduction of lysosomal markers in affected nigral DA neurons, suggesting a defect in lysosome-mediated clearance of α-syn aggregates (5-7).How dysfunction of the autophagy-lysosome pathway (ALP) contributes to the pathogenesis of PD remains unclear. Under physiological conditions, α-syn is degraded by the ubiquitinproteasome system and the ALP, including macroautophagy and chaperone-mediated autophagy (6,(8)(9)(10)(11)(12). In cases of α-syn overload, however, misfolded or mutated α-syn fails to be processed and α-syn clearance by chaperone-mediated autophagy is blocked (12)(13)(14)(15). In this situation, processing of excess α-syn, or toxic α-syn species, will depend on the functional integrity of the macroautophagy pathway (14). In support, it has been shown that mice deficient in one of the autophagy-related (atg) proteins develop neurodegeneration, and that deficiency in atg7 or the PD-associated protein PARK9 (ATP13A2, a lysosomal ATPase) causes PD-like neurodegeneration, both in vitro and in vivo (7,(16)(17)(18)(19). In humans, PD has been genetically linked to the rare lysosomal storage diseases, Gaucher disease a...

Zinc efflux through lysosomal exocytosis prevents zinc-induced toxicity

“…4B (Kukic et al, 2013)], or through its secretion mediated by lysosomal fusion with the plasma membrane. The latter has recently gained a lot of attention as detoxification mechanism in the lysosomal storage diseases (Fraldi et al, 2010;Medina et al, 2011;Palmieri et al, 2011;Decressac et al, 2013;Pastore et al, 2013). The next set of experiments tested the role of lysosomes in Zn 2+ secretion.…”

Activation of Peroxisome Proliferator-activated Receptor α Induces Lysosomal Biogenesis in Brain Cells

“…According to Tsunemi et al (55), activation of TFEB via PGC1␣ may result in increased htt turnover and the elimination of protein aggregates. There are reports suggesting a link between ␣-synuclein toxicity and impaired function of TFEB and identified TFEB as a target for neuroprotective therapy in Parkinson disease (56). TFEB activation has also been shown to enhance the folding, trafficking, and activity of a destabilized glucocerebrosidase variant in Gaucher disease.…”

MiT/TFE transcription factors are activated during mitophagy downstream of Parkin and Atg5

“…Notably, mutations in the lysosomal enzyme glucocerebrosidase, which cause the lysosomal storage disorder (LSD) Gaucher disease, are a risk factor for PD (Sidransky et al, 2009). Overexpression of TFEB has been used to promote clearance of toxic storage materials and rescue cellular and protein homeostasis in several animal and cell models of LSDs and neurodegenerative disorders, including Gaucher disease and Tay-Sachs disease (Song et al, 2013); Pompe disease Spampanato et al, 2013); multiple sulfatase deficiency, Batten disease, and mucopolysaccharidosis type IIIA ); Alzheimer's disease (Polito et al, 2014); Huntington disease (Tsunemi et al, 2012); and PD (Decressac et al, 2013). Overall, this study identifies a novel way in which TFEB and its homologues can be activated by the PINK1-Parkin pathway and may open new avenues for targeting therapeutics to treat diseases such as PD and LSDs.…”