Buffering of cytosolic calcium plays a neuroprotective role by preserving the autophagy-lysosome pathway during MPP-induced neuronal death.

Parkinson's disease (PD) is a chronic neurodegenerative disease with no cure. Calbindin, a Ca-buffering protein, has been suggested to have a neuroprotective effect in the brain tissues of PD patients and in experimental models of PD. However, the underlying mechanisms remain elusive. Here, we report that in 1-methyl-4-phenylpyridinium (MPP)-induced culture models of PD, the buffering of cytosolic Ca by calbindin-D28 overexpression or treatment with a chemical Ca chelator reversed impaired autophagic flux, protecting cells against MPP-mediated neurotoxicity. When cytosolic Ca overload caused by MPP was ameliorated, the MPP-induced accumulation of autophagosomes decreased and the autophagic flux significantly increased. In addition, the accumulation of damaged mitochondria and p62-positive ubiquitinated protein aggregates, following MPP intoxication, was alleviated by cytosolic Ca buffering. We showed that MPP treatment suppressed autophagic degradation via raising the lysosomal pH and therefore reducing cytosolic Ca elevation restored the lysosomal pH acidity and normal autophagic flux. These results support the notion that functional lysosomes are required for Ca-mediated cell protection against MPP-mediated neurotoxicity. Thus, our data suggest a novel process in which the modulation of Ca confers neuroprotection via the autophagy-lysosome pathway. This may have implications for the pathogenesis and future therapeutic targets of PD.