Abstract
AIM: Missense mutations of dynactin subunit p150(Glued) have been associated with multiple neurodegenerative diseases, including Perry syndrome, characterized by inherited parkinsonism, depression, weight loss, and hypoventilation. The current study investigated how the pathogenic mutant p150(Glued) affects the integrity and function of the nigrostriatal dopaminergic (DA) pathway in vivo. METHODS: Using a tetracycline-controlled transcriptional regulation system, transgenic mouse models were generated with selective overexpression of wild-type, motor neuron disease-related G59S mutant, or Perry syndrome-related G71R mutant human p150(Glued) in midbrain DA neurons. A series of behavioral, neuropathological, neurochemical, electrochemical, and biochemical studies were performed on the mice to examine and compare the pathogenic impact of the two mutant p150(Glued) on the survival and function of midbrain DA neurons. RESULTS: Compared with non-transgenic control mice, transgenic mice overexpressing wild-type human p150(Glued) showed neither motor phenotypes nor pathological, functional, or biochemical abnormalities of the nigrostriatal DA pathway. Transgenic mice overexpressing G59S mutant p150(Glued) displayed weight loss, motor deficits, early-onset defects in dopamine transmission, and early-onset loss of DA neurons and axons. Transgenic mice overexpressing G71R p150(Glued) mutant exhibited hyperactivities, impaired motor coordination, early-onset dysfunction of dopamine uptake, and late-onset loss of DA neurons and axons. In addition, overexpression of either G59S or G71R mutant p150(Glued) in midbrain DA neurons preferentially downregulated the expression of dopamine transporter at dopaminergic axon terminals. Furthermore, G59S mutant p150(Glued) rather than G71R mutant p150(Glued) formed aggregates in midbrain DA neurons in vivo, and the aggregates trapped dynein/dynactin, co-localized with lysosomes, and upregulated ubiquitination. CONCLUSION: These findings demonstrate that selective expression of either G59S or G71R mutant p150(Glued) in mouse midbrain DA neurons leads to progressive degeneration of the nigrostriatal DA pathway and indicate that G59S and G71R mutant p150(Glued) exhibit differential pathogenic impact on the survival and function of midbrain DA neurons in vivo.