Abstract
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.
Highlights
Parkinson’s disease (PD) is a multifactorial neurodegenerative disease characterized by the cardinal features of resting tremor, bradykinesia and muscle rigidity, as well as non-motor symptoms, which can develop years before motor deficits
In PD patients, we found that Transcription factor E3 (TFE3) staining in the nuclei was reduced in the substantia nigra pars compacta (SN) dopaminergic neurons (Figure 1A)
These results suggest that the transcriptional activity of TFE3 is repressed in SN dopaminergic neurons of PD patients
Summary
Parkinson’s disease (PD) is a multifactorial neurodegenerative disease characterized by the cardinal features of resting tremor, bradykinesia and muscle rigidity, as well as non-motor symptoms, which can develop years before motor deficits. Common pathological features of PD are selective and progressive cell death of dopaminergic neurons in the substantia nigra pars compacta (SN). PD is recognized by more widespread pathology in other brain regions and it involves non-dopaminergic neurons as well. The molecular pathogenesis of PD includes various factors, such as impaired protein homeostasis, oxidative stress, mitochondria dysfunction and neuron inflammation. In recent years, growing evidence suggests that autophagy is involved in PD. Impaired autophagy has been verified in dopaminergic neurons of PD patients. Accumulation of autophagic vacuoles has been described in the SN of PD patients (Fowler and Moussa, 2018), suggesting autophagy flux disruption. Lysosomal dysfunction was indicated by decreased protein levels of Lysosomal-associated membrane protein type 1 (Lamp1), a lysosomal marker, and Cathepsin D (CatD), a lysosomal protease, in the TFE3 Mediates Autophagy in PD
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