TFE3-Mediated Autophagy is Involved in Dopaminergic Neurodegeneration in Parkinson’s Disease

Impairment of autophagy has been strongly implicated in the progressive loss of nigral dopaminergic neurons in Parkinson’s disease (PD). Transcription factor E3 (TFE3), an MiTF/TFE family transcription factor, has been identified as a master regulator of the genes that are associated with lysosomal biogenesis and autophagy. However, whether TFE3 is involved in parkinsonian neurodegeneration remains to be determined. In this study, we found decreased TFE3 expression in the nuclei of the dopaminergic neurons of postmortem human PD brains. Next, we demonstrated that TFE3 knockdown led to autophagy dysfunction and neurodegeneration of dopaminergic neurons in mice, implying that reduction of nuclear TFE3 may contribute to autophagy dysfunction-mediated cell death in PD. Further, we showed that enhancement of autophagy by TFE3 overexpression dramatically reversed autophagy downregulation and dopaminergic neurons loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Taken together, these findings demonstrate that TFE3 plays an essential role in maintaining autophagy and the survival of dopaminergic neurons, suggesting TFE3 activation may serve as a promising strategy for PD therapy.

Programmed Death-1 Deficiency Aggravates Motor Dysfunction In MPTP Model of Parkinson's Disease By Inducing Microglial Activation And Neuroinflammation In Mice

Abundant reactive gliosis and neuroinflammation are typical pathogenetic hallmarks of brains in Parkinson’s disease (PD) patients, but regulation mechanisms are poorly understood. We are interested in role of programmed death-1 (PD-1) in glial reaction, neuroinflammation and neuronal injury in PD pathogenesis. Using PD mouse model and PD-1 knockout (KO) mice, we designed wild-type-control (WT-CON), WT-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (WT-MPTP), PD-1-KO-control (KO-CON) and PD-1-KO-MPTP (KO-MPTP), and observed motor dysfunction of animal, morphological distribution of PD-1-positive cells, dopaminergic neuronal injury, glial activation and generation of inflammatory cytokines in midbrains by motor behavior detection, immunohistochemistry and western blot. WT-MPTP mouse model exhibited decrease of PD-1/Iba1-positive microglial cells in the substantia nigra compared with WT-CON mice. By comparison of four groups, PD-1 deficiency showed exacerbation in motor dysfunction of animals, decreased expression of TH protein and TH-positive neuronal protrusions. PD-1 deficiency enhanced microglial activation, production of pro-inflammatory cytokines like inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-1β and interleukin-6, and expression and phosphorylation of AKT and ERK1/2 in the substantia nigra of MPTP model. We concluded that PD-1 deficiency could aggravate motor dysfunction of MPTP mouse model by inducing microglial activation and neuroinflammation in midbrains, suggesting that PD-1 signaling abnormality might be possibly involved in PD pathogenesis.

KDS2010, a Newly Developed Reversible MAO-B Inhibitor, as an Effective Therapeutic Candidate for Parkinson’s Disease

Monoamine oxidase-B (MAO-B) is a well-established therapeutic target for Parkinson’s disease (PD); however, previous clinical studies on currently available irreversible MAO-B inhibitors have yielded disappointing neuroprotective effects. Here, we tested the therapeutic potential of KDS2010, a recently synthesized potent, selective, and reversible MAO-B inhibitor in multiple animal models of PD. We designed and synthesized a series of α-aminoamide derivatives and found that derivative KDS2010 exhibited the highest potency, specificity, reversibility, and bioavailability (> 100%). In addition, KDS2010 demonstrated significant neuroprotective and anti-neuroinflammatory efficacy against nigrostriatal pathway destruction in the mouse MPTP model of parkinsonism. Treatment with KDS2010 also alleviated parkinsonian motor dysfunction in 6-hydroxydopamine-induced and A53T mutant α-synuclein overexpression rat models of PD. Moreover, KDS2010 showed virtually no toxicity or side effects in non-human primates. KDS2010 could be a next-generation therapeutic candidate for PD.

PD-1 Knockout Aggravates Motor Dysfunction In The MPTP Model of Parkinson's Disease By Inducing Microglial Activation And Neuroinflammation In Mice

Background: Abundant microglial reaction and neuroinflammation are typical pathogenetic hallmark of brains in Parkinson’s disease (PD) patients, but regulation mechanisms are poorly understood. In this study, the promoting effects of PD-1-difficiency on microglial activation, neuroinflammation and motor dysfunction were identified using PD animal model.Methods: Using C57 wild-type (WT), PD-1 knockout (KO) and MPTP model, we designed WT-control, KO-control, WT-MPTP and KO-MPTP groups. Motor dysfunction of animal, distribution of PD-1-positive cells, dopaminergic neuronal survival, glial cell activation and generation of inflammatory cytokines in midbrains were observed by behavior detection, immunohistochemistry and western blot methods. Results: Microglial cells showing PD-1/Iba1 double-positivity were numerously distributed in the substantia nigra of control whereas they decreased in MPTP model. Compared with WT-MPTP, KO-MPTP mice exacerbated in their motor dysfunction, decreased level of TH expression and decreased TH-positive neuronal protrusions. Microglial cell activation and expression of proinflammatory cytokine iNOS, TNF-α, IL-1β and IL-6 significantly increased, and levels and phosphorylation of AKT and ERK1/2 were also elevated in KO-MPTP mice. Conclusions: PD-1 knockout could aggravate motor dysfunction of MPTP mouse model by promoting microglial activation and neuroinflammation in midbrains, suggesting that PD-1 signaling abnormality might be involved in PD pathogenesis or progression.