BAG1 is neuroprotective in in vivo and in vitro models of Parkinson's disease.

Abstract

Bcl-2-associated athanogene-1 (BAG1) is a multifunctional protein comprising co-chaperone function, increasing Hsp70 foldase activity and chaperone-dependent protein degradation of misfolded substrates, with anti-apoptotic activity. It is neuroprotective in different models of neurological diseases, like cerebral ischemia and Huntington's disease. In the context of Parkinson's disease, it has recently been shown to restore DJ-1 function in an in vitro model of hereditary Parkinson's disease. Here, we demonstrate that BAG1 overexpression in SH-SY5Y cells reduces toxicity after transfection of disease-related α-synuclein mutants. Furthermore, it protects from rotenone-induced cell death in vitro and ameliorates neuronal demise in an in vivo 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) model for Parkinson's disease after adeno-associated virus (AAV)-mediated BAG1 gene transfer into the substantia nigra in mice but showed no protective effects in an in vitro 6-hydroxidopamine model. In conclusion, we present BAG1 as a potential therapeutic target in Parkinson's disease.