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Idiopathic Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, which is associated with neuroinflammation and reactive gliosis. The underlying cause of PD and the concurrent neuroinflammation are not well understood. In this study, we utilize human and murine neuronal lines, stem cell‐derived dopaminergic neurons, and mice to demonstrate that three previously identified genetic risk factors for PD, namely SATB1, MIR22HG, and GBA, are components of a single gene regulatory pathway. Our findings indicate that dysregulation of this pathway leads to the upregulation of glucocerebrosides (GluCer), which triggers a cellular senescence‐like phenotype in dopaminergic neurons. Specifically, we discovered that downregulation of the transcriptional repressor SATB1 results in the derepression of the microRNA miR‐22‐3p, leading to decreased GBA expression and subsequent accumulation of GluCer. Furthermore, our results demonstrate that an increase in GluCer alone is sufficient to impair lysosomal and mitochondrial function, thereby inducing cellular senescence. Dysregulation of the SATB1‐MIR22‐GBA pathway, observed in both PD patients and normal aging, leads to lysosomal and mitochondrial dysfunction due to the GluCer accumulation, ultimately resulting in a cellular senescence‐like phenotype in dopaminergic neurons. Therefore, our study highlights a novel pathway involving three genetic risk factors for PD and provides a potential mechanism for the senescence‐induced neuroinflammation and reactive gliosis observed in both PD and normal aging. [ABSTRACT FROM AUTHOR]

Acetylcholine, the first chemical to be identified as a neurotransmitter, is packed in synaptic vesicles by the activity of VAChT (vesicular acetylcholine transporter). A decrease in VAChT expression has been reported in a number of diseases, and this has consequences for the amount of acetylcholine loaded in synaptic vesicles as well as for neurotransmitter release. Several genetically modified mice targeting the VAChT gene have been generated, providing novel models to understand how changes in VAChT affect transmitter release.Asurprising finding is that most cholinergic neurons in the brain also can express a second type of vesicular neurotransmitter transporter that allows these neurons to secrete two distinct neurotransmitters. Thus a given neuron can use two neurotransmitters to regulate different physiological functions. In addition, recent data indicate that non-neuronal cells can also express the machinery used to synthesize and release acetylcholine. Some of these cells rely on VAChT to secrete acetylcholine with potential physiological consequences in the periphery. Hence novel functions for the oldest neurotransmitter known are emerging with the potential to provide new targets for the treatment of several pathological conditions. [ABSTRACT FROM AUTHOR]

Ongoing, early-stage clinical trials illustrate the translational potential of human pluripotent stem cell (hPSC)-based cell therapies in Parkinson's disease (PD). However, an unresolved challenge is the extensive cell death following transplantation. Here, we performed a pooled CRISPR-Cas9 screen to enhance postmitotic dopamine neuron survival in vivo. We identified p53-mediated apoptotic cell death as a major contributor to dopamine neuron loss and uncovered a causal link of tumor necrosis factor alpha (TNF-α)-nuclear factor κB (NF-κB) signaling in limiting cell survival. As a translationally relevant strategy to purify postmitotic dopamine neurons, we identified cell surface markers that enable purification without the need for genetic reporters. Combining cell sorting and treatment with adalimumab, a clinically approved TNF-α inhibitor, enabled efficient engraftment of postmitotic dopamine neurons with extensive reinnervation and functional recovery in a preclinical PD mouse model. Thus, transient TNF-α inhibition presents a clinically relevant strategy to enhance survival and enable engraftment of postmitotic hPSC-derived dopamine neurons in PD. [Display omitted] • CRISPR-Cas9 screen identifies p53 in restricting in vivo dopamine neuron survival • TNF-α-NF-κB pathway mediates p53-dependent dopamine neuron death • Cell surface marker screen to enrich human dopamine neurons for translational use • Approved TNF-α inhibitor rescues dopamine neuron survival with in vivo function Transient TNF-α inhibition overcomes a p53-dependent program that restricts the survival of grafted dopamine neurons and offers a clinically relevant strategy to enhance survival and promote functional dopamine neuronal engraftment in cell-based therapies for Parkinson's disease. [ABSTRACT FROM AUTHOR]