Neuron
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T-type calcium channels are essential contributors to the transmission of nociceptive signals in the primary afferent pain pathway. Here, we show that T-type calcium channels are ubiquitinated by WWP1, a plasma-membrane-associated ubiquitin ligase that binds to the intracellular domain III-IV linker region of the Cav3.2 T-type channel and modifies specific lysine residues in this region. ⋯ In vivo knockdown of USP5 or uncoupling USP5 from native Cav3.2 channels via intrathecal delivery of Tat peptides mediates analgesia in both inflammatory and neuropathic mouse models of mechanical hypersensitivity. Altogether, our experiments reveal a cell signaling pathway that regulates T-type channel activity and their role in nociceptive signaling.
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Alzheimer's disease (AD) is a clinically heterogeneous neurodegenerative disease with a strong genetic component. Several genes have been associated with AD risk for nearly 20 years. ⋯ Genome-wide association studies and whole-exome and whole-genome sequencing have revealed more than 20 loci associated with AD risk. These studies have provided insights into the molecular pathways that are altered in AD pathogenesis, which have, in turn, provided insight into novel therapeutic targets.
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Neural stem cells have been adopted to model a wide range of neuropsychiatric conditions in vitro. However, how well such models correspond to in vivo brain has not been evaluated in an unbiased, comprehensive manner. We used transcriptomic analyses to compare in vitro systems to developing human fetal brain and observed strong conservation of in vivo gene expression and network architecture in differentiating primary human neural progenitor cells (phNPCs). ⋯ We also developed and validated a machine learning approach called CoNTExT that identifies the developmental maturity and regional identity of in vitro models. We observed strong differences between in vitro models, including hiPSC-derived neural progenitors from multiple laboratories. This work provides a systems biology framework for evaluating in vitro systems and supports their value in studying the molecular mechanisms of human neurodevelopmental disease.
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The collapse of neural networks important for memory and cognition, including death of neurons and degeneration of synapses, causes the debilitating dementia associated with Alzheimer's disease (AD). We suggest that synaptic changes are central to the disease process. ⋯ Further, the march of neurofibrillary tangles through brain circuits appears to take advantage of recently described mechanisms of transsynaptic spread of pathological forms of tau. These two key phenomena, synapse loss and the spread of pathology through the brain via synapses, make it critical to understand the physiological and pathological roles of amyloid beta and tau at the synapse.
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Numerous pain-producing (pronociceptive) receptors signal via phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. However, it is currently unknown which lipid kinases generate PIP2 in nociceptive dorsal root ganglia (DRG) neurons and if these kinases regulate pronociceptive receptor signaling. Here, we found that phosphatidylinositol 4-phosphate 5 kinase type 1C (PIP5K1C) is expressed at higher levels than any other PIP5K and, based on experiments with Pip5k1c(+/-) mice, generates at least half of all PIP2 in DRG neurons. ⋯ We identified a small molecule inhibitor of PIP5K1C (UNC3230) in a high-throughput screen. UNC3230 lowered PIP2 levels in DRG neurons and attenuated hypersensitivity when administered intrathecally or into the hindpaw. Our studies reveal that PIP5K1C regulates PIP2-dependent nociceptive signaling and suggest that PIP5K1C is a therapeutic target for chronic pain.