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

摘要

Parkinson's disease (PD) is a chronic neurodegenerative disease with no cure. Calbindin, a Casup2+/sup-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 (MPPsup+/sup)-induced culture models of PD, the buffering of cytosolic Casup2+/sup by calbindin-D28 overexpression or treatment with a chemical Casup2+/sup chelator reversed impaired autophagic flux, protecting cells against MPPsup+/sup-mediated neurotoxicity. When cytosolic Casup2+/sup overload caused by MPPsup+/sup was ameliorated, the MPPsup+/sup-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 MPPsup+/sup intoxication, was alleviated by cytosolic Casup2+/sup buffering. We showed that MPPsup+/sup treatment suppressed autophagic degradation via raising the lysosomal pH and therefore reducing cytosolic Casup2+/sup elevation restored the lysosomal pH acidity and normal autophagic flux. These results support the notion that functional lysosomes are required for Casup2+/sup-mediated cell protection against MPPsup+/sup-mediated neurotoxicity. Thus, our data suggest a novel process in which the modulation of Casup2+/sup confers neuroprotection via the autophagy-lysosome pathway. This may have implications for the pathogenesis and future therapeutic targets of PD.