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(2+)-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(2+) by calbindin-D28 overexpression or treatment with a chemical Ca(2+) chelator reversed impaired autophagic flux, protecting cells against MPP(+)-mediated neurotoxicity. When cytosolic Ca(2+) 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(2+) buffering. We showed that MPP(+) treatment suppressed autophagic degradation via raising the lysosomal pH and therefore reducing cytosolic Ca(2+) elevation restored the lysosomal pH acidity and normal autophagic flux. These results support the notion that functional lysosomes are required for Ca(2+)-mediated cell protection against MPP(+)-mediated neurotoxicity. Thus, our data suggest a novel process in which the modulation of Ca(2+) confers neuroprotection via the autophagy-lysosome pathway. This may have implications for the pathogenesis and future therapeutic targets of PD.