Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy

Yang Q., et al. Science 323(5910): 124-127 (2009)

Speaker: Po-Shun Wang (王柏舜)                 Time: 14:00-15:00, Mar. 11, 2009

Commentator: Dr. Li-Jin Hsu (徐麗君老師)  Place: Room 601

Abstract:

Chaperone-mediated autophagy (CMA) is a selective mechanism for the degradation of cytosolic proteins in lysosomes ⁽¹⁾. The process involves recognition of substrate proteins with specific KFERQ-like motif by heat shock protein of 70 kda (Hsc 70) and subsequently binds to the receptor, lysosome-associated membrane protein type 2a (Lamp 2a), on the lysosomal membrane. The members of myocyte enhancer factor 2 (MEF2) transcription factors are highly expressed in neurons and regulate genes that control neuronal differentiation and survival ⁽²⁾. However, little is known about the direct mechanism by which CMA modulates neuronal fate. Here, the authors showed that CMA plays a major role in regulating the activity of MEF2D. Moreover, they also unraveled MEF2D is constantly exported to the cytoplasm, and interacts with Hsc70 for lysosomal degradation. Instead, Inhibition of CMA induces the accumulation of inactive MEF2D in the cytoplasm. α-synuclein, which is an abundant neuronal protein that has been linked to neurodegenerative diseases, serves as a CMA substrate and a risk factor of Parkinson’s disease (PD) ⁽³⁾. The authors demonstrated that cytoplasmic MEF2D level is significantly increased in the brains of α-synuclein transgenic mice and PD patients. Intriguingly, both wild-type and PD-associated mutant α-synuclein (A53T) inhibit MEF2D function and cause reduction of neuronal viability, suggesting that blockade of CMA is implicated in PD pathogenesis. All together, these findings reveal that CMA modulates the neuronal survival machinery and provides a new insight for PD therapy and drug design.

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