{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Junctophilin‐3 (JPH3) is predominantly expressed in neurons where it is a key component of junctional membrane complexes that physically couple the plasma membrane to intracellular calcium stores. This spatial organization facilitates precise calcium signaling, which is essential for neuronal excitability and recovery from excitotoxic challenges—for instance, JPH3 expression is up‐regulated along with other activity‐inducible genes after sleep loss to help counteract glutamate‐induced hyperactivity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition to its physiological role in calcium homeostasis and signal integration, genetic alterations in JPH3 have been robustly linked to a Huntington disease–like phenotype (HDL2). Pathological CTG/CAG repeat expansions in the JPH3 gene give rise to toxic RNA species, aberrant protein products, and reduced levels of full‐length JPH3, thus impairing neuronal function and leading to progressive neurodegeneration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "5"}]}, {"type": "t", "text": " Animal models further confirm that loss or reduction of JPH3 disrupts neural circuit function and manifests as motor coordination deficits."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " At the subcellular level, JPH3, together with its neuronal counterpart JPH4, participates in assembling multi‐protein complexes (e.g., including L-type Ca²⁺ channels, ryanodine receptors, and Ca²⁺-activated K⁺ channels) that fine-tune calcium dynamics in hippocampal neurons."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Beyond the central nervous system, JPH3 is also expressed in pancreatic β cells, where it modulates calcium release and mitochondrial interactions to regulate glucose-stimulated insulin secretion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Moreover, population studies indicate that while CTG repeat lengths in the JPH3 gene are polymorphic in healthy individuals"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", pathological expansions are predominantly observed in individuals of African ancestry and contribute significantly to the HDL2 phenotype."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore the multifunctional role of JPH3 in regulating intracellular calcium dynamics, maintaining neuronal excitability, and ensuring proper neurophysiological homeostasis. Disruptions of its normal function, whether by altered expression or repeat expansion, contribute to complex neurodegenerative and, potentially, metabolic dysfunctions.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Stéphanie Maret, Stéphane Dorsaz, Laure Gurcel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Homer1a is a core brain molecular correlate of sleep loss."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0710131104"}], "href": "https://doi.org/10.1073/pnas.0710131104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18077435"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18077435"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Giovanni Stevanin, Hiroto Fujigasaki, Anne-Sophie Lebre, et al. 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