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Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the degeneration of dopamine (DA) and non-DA neurons, the almost uniform presence of Lewy bodies, and motor deficits. Although the majority of PD is sporadic, specific genetic defects in rare familial cases have provided unique insights into the pathogenesis of PD.(More)
Leucine-rich repeat kinase-2 (LRRK2) mutations are a common cause of Parkinson's disease. Here we identify inhibitors of LRRK2 kinase that are protective in in vitro and in vivo models of LRRK2-induced neurodegeneration. These results establish that LRRK2-induced degeneration of neurons in vivo is kinase dependent and that LRRK2 kinase inhibition provides a(More)
c-Abl is activated in the brain of Parkinson's disease (PD) patients and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice where it inhibits parkin through tyrosine phosphorylation leading to the accumulation of parkin substrates, and neuronal cell death. In the present study, we evaluated the in vivo efficacy of nilotinib, a brain(More)
Autosomal-recessive juvenile parkinsonism (AR-JP) is caused by loss-of-function mutations of the parkin gene. Parkin, a RING-type E3 ubiquitin ligase, is responsible for the ubiquitination and degradation of substrate proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). Accordingly, the abnormal accumulation of(More)
The defining pathogenic feature of Parkinson's disease is the age-dependent loss of dopaminergic neurons. Mutations and inactivation of parkin, an ubiquitin E3 ligase, induce Parkinson's disease through accumulation of pathogenic substrates. We found that transgenic overexpression of a parkin substrate, aminoacyl-tRNA synthetase complex interacting(More)
Increases in S-nitrosylation and inactivation of the neuroprotective ubiquitin E3 ligase, parkin, in the brains of patients with Parkinson's disease are thought to be pathogenic and suggest a possible mechanism linking parkin to sporadic Parkinson's disease. Here we demonstrate that physiologic modification of parkin by hydrogen sulfide, termed(More)
Aggregation of α-synuclein contributes to the formation of Lewy bodies and neurites, the pathologic hallmarks of Parkinson disease (PD) and α-synucleinopathies. Although a number of human mutations have been identified in familial PD, the mechanisms that promote α-synuclein accumulation and toxicity are poorly understood. Here, we report that hyperactivity(More)
One of the tuberous sclerosis complex (TSC) gene products, tuberin is assumed to be the functional component, being involved in a wide variety of cellular processes. Here, we report for the first time that tuberin dysfunction may represent a mechanism for neuronal damage in Alzheimer's disease (AD), Parkinson's disease with dementia (PD/DLB), and a mouse(More)
Recent advances in 3D culture systems have led to the generation of brain organoids that resemble different human brain regions; however, a 3D organoid model of the midbrain containing functional midbrain dopaminergic (mDA) neurons has not been reported. We developed a method to differentiate human pluripotent stem cells into a large multicellular(More)
Increases in S-nitrosylation and inactivation of the neuroprotective ubiquitin E3 ligase, parkin, in the brains of patients with Parkinson's Disease (PD) are thought to be pathogenic and suggest a possible mechanism linking parkin to sporadic PD. Here we demonstrate that physiologic modification of parkin by hydrogen sulfide (H 2 S), termed sulfhydration,(More)