FKBP51 inhibition ameliorates neurodegeneration and motor dysfunction in the neuromelanin-SNCA mouse model of Parkinson's disease.

Parkinson's disease (PD) is characterized by the loss of neuromelanin (NM)-containing dopaminergic (DA) neurons in the substantia nigra (SN) pars compacta (SNpc) and the buildup of α-synuclein (α-syn) inclusions, called Lewy bodies. To investigate the roles of NM and α-syn in DA neuron degeneration, we modeled PD by inducing NM accumulation in a humanized α-syn mouse model (Snca(-); PAC-Tg(SNCA(WT))) via the expression of human tyrosinase in the SN. We found that this mouse strain develops naturally progressive motor dysfunction and dopaminergic neuronal loss in the SN with aging. Upon tyrosinase injection, NM-containing neurons developed p62 and ubiquitin inclusions. Furthermore, the upregulation of genes associated with microglial activation in the midbrain indicated a role of pro-inflammatory factors in neurodegeneration. Midbrain RNA sequencing confirmed the microglial response and identified Fkbp5 as one of the more dysregulated genes. Next, we showed that FKBP51(51 kDa) was significantly upregulated with aging and in PD human brains. Pharmacological treatment with SAFit2, a potent FKBP51 inhibitor, led to a reduction in ubiquitin-positive inclusions, prevention of neurodegeneration in the SNpc, and improved motor function in NM-SNCAWT mice. These results highlight the critical role of FKBP51 in PD and propose SAFit2 as a promising therapeutic candidate for reducing neurodegeneration in PD.