Parkinson’s disease(PD)is the most common neurodegenerative movement disorder,characterized primarily by the loss of dopaminergic neurons in substantia nigra.The pathogenic mechanisms of PD remain unclear,and no effe...Parkinson’s disease(PD)is the most common neurodegenerative movement disorder,characterized primarily by the loss of dopaminergic neurons in substantia nigra.The pathogenic mechanisms of PD remain unclear,and no effective therapy currently exists to stop neurodegeneration in this debilitating disease.The identification of mutations in mitochondrial serine/threonine kinase PINK1 or E3 ubiquitin-protein ligase parkin as the cause of autosomal recessive PD opens up new avenues for uncovering neuroprotective pathways and PD pathogenic mechanisms.Recent studies reveal that PINK1 translocates to the outer mitochondrial membrane in response to mitochondrial depolarization and phosphorylates ubiquitin at the residue Ser65.The phosphorylated ubiquitin serves as a signal for activating parkin and recruiting autophagy receptors to promote clearance of damaged mitochondria via mitophagy.Emerging evidence has begun to indicate a link between impaired ubiquitin phosphorylation-dependent mitophagy and PD pathogenesis and supports the potential of Ser65-phosphorylated ubiquitin as a biomarker for PD.The new mechanistic insights and phenotypic screens have identified multiple potential therapeutic targets for PD drug discovery.This review highlights recent advances in understanding ubiquitin phosphorylation in mitochondrial quality control and PD pathogenesis and discusses how these findings can be translated into novel approaches for PD diagnostic and therapeutic development.展开更多
Hypertonia is a neurological dysfunction associated with a number of central nervous system disorders, including cerebral palsy, Parkinson＇s disease, dystonia, and epilepsy. Genetic studies have identified a homozygo...Hypertonia is a neurological dysfunction associated with a number of central nervous system disorders, including cerebral palsy, Parkinson＇s disease, dystonia, and epilepsy. Genetic studies have identified a homozygous truncation mutation in Trakl that causes hypertonia in mice. Moreover, elevated Trakl protein expression is associated with several types of cancers and variants in Trakl are linked to childhood absence epilepsy in humans. Despite the importance of Trakl in health and disease, the mechanisms of Trakl action remain unclear and the pathogenic effects of Trakl mutation are unknown. Here we report that Trakl has a crucial function in regulation of mitochondrial fusion. Depletion of Trakl inhibits mitochondrial fusion, result- ing in mitochondrial fragmentation, whereas overex- pression of Trakl elongates and enlarges mitochondria. Our analyses revealed that Trakl interacts and colocal- izes with mitofusins on the outer mitochondrial mem- brane and functions with mitofusins to promote mitochondrial tethering and fusion. Furthermore, Trakl is required for stress-induced mitochondrial hyperfu- sion and pro-survival response. We found that hyper- tonia-associated mutation impairs Trakl mitochondrial localization and its ability to facilitate mitochondrial tethering and fusion. Our findings uncover a novel function of Trakl as a regulator of mitochondrial fusion and provide evidence linking dysregulated mitochon- drial dynamics to hypertonia pathogenesis.展开更多
基金Work in the authors’laboratories is supported by grants from National Institutions of Health(NS093550,GM103613,and NS092343)a pilot grant award from NIH-funded Emory Udall Parkinson’s Disease Center(P50 NS071669).
文摘Parkinson’s disease(PD)is the most common neurodegenerative movement disorder,characterized primarily by the loss of dopaminergic neurons in substantia nigra.The pathogenic mechanisms of PD remain unclear,and no effective therapy currently exists to stop neurodegeneration in this debilitating disease.The identification of mutations in mitochondrial serine/threonine kinase PINK1 or E3 ubiquitin-protein ligase parkin as the cause of autosomal recessive PD opens up new avenues for uncovering neuroprotective pathways and PD pathogenic mechanisms.Recent studies reveal that PINK1 translocates to the outer mitochondrial membrane in response to mitochondrial depolarization and phosphorylates ubiquitin at the residue Ser65.The phosphorylated ubiquitin serves as a signal for activating parkin and recruiting autophagy receptors to promote clearance of damaged mitochondria via mitophagy.Emerging evidence has begun to indicate a link between impaired ubiquitin phosphorylation-dependent mitophagy and PD pathogenesis and supports the potential of Ser65-phosphorylated ubiquitin as a biomarker for PD.The new mechanistic insights and phenotypic screens have identified multiple potential therapeutic targets for PD drug discovery.This review highlights recent advances in understanding ubiquitin phosphorylation in mitochondrial quality control and PD pathogenesis and discusses how these findings can be translated into novel approaches for PD diagnostic and therapeutic development.
文摘Hypertonia is a neurological dysfunction associated with a number of central nervous system disorders, including cerebral palsy, Parkinson＇s disease, dystonia, and epilepsy. Genetic studies have identified a homozygous truncation mutation in Trakl that causes hypertonia in mice. Moreover, elevated Trakl protein expression is associated with several types of cancers and variants in Trakl are linked to childhood absence epilepsy in humans. Despite the importance of Trakl in health and disease, the mechanisms of Trakl action remain unclear and the pathogenic effects of Trakl mutation are unknown. Here we report that Trakl has a crucial function in regulation of mitochondrial fusion. Depletion of Trakl inhibits mitochondrial fusion, result- ing in mitochondrial fragmentation, whereas overex- pression of Trakl elongates and enlarges mitochondria. Our analyses revealed that Trakl interacts and colocal- izes with mitofusins on the outer mitochondrial mem- brane and functions with mitofusins to promote mitochondrial tethering and fusion. Furthermore, Trakl is required for stress-induced mitochondrial hyperfu- sion and pro-survival response. We found that hyper- tonia-associated mutation impairs Trakl mitochondrial localization and its ability to facilitate mitochondrial tethering and fusion. Our findings uncover a novel function of Trakl as a regulator of mitochondrial fusion and provide evidence linking dysregulated mitochon- drial dynamics to hypertonia pathogenesis.
