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α-Synuclein (α-syn) aggregation is a key event in Parkinson’s disease (PD). Mutations in glycosphingolipid (GSL)-degrading glucocerebrosidase are risk factors for PD, indicating that disrupted GSL clearance plays a key role in α-syn aggregation. However, the mechanisms of GSL-induced aggregation are not completely understood. We document the presence of physiological α-syn conformers in human midbrain...
Parkinson’s disease is characterized by the progressive loss of midbrain dopamine neurons. Dopamine replacement therapy with levodopa alleviates parkinsonian motor symptoms but is complicated by the development of involuntary movements, termed levodopa-induced dyskinesia (LID). Aberrant activity in the striatum has been hypothesized to cause LID. Here, to establish a direct link between striatal activity...
Striatal dopamine signaling is differentially regulated along the dorso-ventral axis, but how these differences are encoded by dopamine receptors is unknown. In this issue of Neuron, Marcott et al. (2018) show that dopamine activates D2 receptors in regionally distinct ways and dissect the underlying mechanisms behind striatal D2 heterogeneity.
Parkinson’s disease patients report disturbed sleep patterns long before motor dysfunction. Here, in parkin and pink1 models, we identify circadian rhythm and sleep pattern defects and map these to specific neuropeptidergic neurons in fly models and in hypothalamic neurons differentiated from patient induced pluripotent stem cells (iPSCs). Parkin and Pink1 control the clearance of mitochondria by...
Parkinson’s disease patients report sleep disturbances well ahead of motor symptoms. In this issue of Neuron, Valadas et al. (2018) report that the disease genes pink1 and parkin exert novel, cell-type-specific effects to modulate ER-mitochondria contacts, neuropeptidergic transmission, and sleep patterns.
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