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Neurodegeneration begins however several years before clinical onset of motor, cognitive or autonomic symptoms. The isolated form of REM sleep behavior disorder (RBD), a parasomnia with dream enactment behaviors and excessive muscle activity during REM sleep, is an early stage synucleinopathy. The neurophysiological hallmark of RBD is REM sleep without atonia (RWSA), i.e. the loss of physiological muscle atonia during REM sleep. RBD pathophysiology is not fully clarified yet, but clinical and basic science suggest that \u0251-syn pathology begins in the lower brainstem where REM atonia circuits are located, including the sublaterodorsal tegmental\/subcoeruleus nucleus and the ventral medulla, then propagates rostrally to brain regions such as the substantia nigra, limbic system, cortex. Genetically, there is only a partial overlap between RBD, PD and DLB, and individuals with iRBD may represent a specific subpopulation. A genome-wide association study identified five loci, which all seem to revolve around the\n                    <jats:italic>GBA1<\/jats:italic>\n                    pathway. iRBD patients often show subtle motor, cognitive, autonomic and\/or sensory signs, neuroimaging alterations as well as biofluid and tissue markers of neurodegeneration (in particular pathologic \u03b1-synuclein aggregates), which can be useful for risk stratification. Patients with iRBD represent thus the ideal population for neuroprotective\/neuromodulating trials. This review provides insights into these aspects, highlighting and substantiating the central role of iRBD in treatment development strategies for synucleinopathies.\n                  <\/jats:p>","DOI":"10.1186\/s13024-025-00809-0","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T13:17:19Z","timestamp":1739279839000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["From mechanisms to future therapy: a synopsis of isolated REM sleep behavior disorder as early synuclein-related disease"],"prefix":"10.1186","volume":"20","author":[{"given":"Ambra","family":"Stefani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Antelmi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Arnaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Arnulf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"During","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"H\u00f6gl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele M. 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RBP is supported by grants from Fonds de la Recherche en Sante, grants from Canadian Institute of Health Research, the Michael J. Fox Foundation, the Webster Foundation, Roche, and the National Institute of Health; RBP reports personal fees from Takeda, Biogen, Abbvie, Curasen, Lilly, Novartis, Eisai, Paladin, Merck, Vaxxinity, Korro, Bristol Myers Squibb and the International Parkinson and Movement Disorders Society, outside the submitted work. MMTH is supported by grants from Parkinson\u2019s UK, Oxford NIHR Biomedical Research Centre, University of Oxford, Michael J Fox Foundation, H2020 European Union and the PSP Association. She is an advisory founder of NeuHealth Digital Ltd (company number: 14492037), a digital biomarker platform to remotely manage condition progression for Parkinson\u2019s disease. ZG received consultancy fees from Lysosomal Therapeutics Inc. (LTI), Idorsia, Prevail Therapeutics, Ono Therapeutics, Denali, Handl Therapeutics, Neuron23, Bial Biotech, Bial, UCB, Capsida, Vanqua bio, Congruence Therapeutics, Takeda, Jazz pharmaceuticals, Guidepoint, Lighthouse and Deerfield.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"19"}}