From mechanisms to future therapy: a synopsis of isolated REM sleep behavior disorder as early synuclein-related disease
Abstract Parkinson disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy are synucleinopathies, characterized by neuronal loss, gliosis and the abnormal deposition of α-synuclein in vulnerable areas of the nervous system. Neurodegeneration begins however several years before clin...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-02-01
|
| Series: | Molecular Neurodegeneration |
| Online Access: | https://doi.org/10.1186/s13024-025-00809-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850024785597169664 |
|---|---|
| author | Ambra Stefani Elena Antelmi Dario Arnaldi Isabelle Arnulf Emmanuel During Birgit Högl Michele M. T. Hu Alex Iranzo Russell Luke John Peever Ronald B. Postuma Aleksandar Videnovic Ziv Gan-Or |
| author_facet | Ambra Stefani Elena Antelmi Dario Arnaldi Isabelle Arnulf Emmanuel During Birgit Högl Michele M. T. Hu Alex Iranzo Russell Luke John Peever Ronald B. Postuma Aleksandar Videnovic Ziv Gan-Or |
| author_sort | Ambra Stefani |
| collection | DOAJ |
| description | Abstract Parkinson disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy are synucleinopathies, characterized by neuronal loss, gliosis and the abnormal deposition of α-synuclein in vulnerable areas of the nervous system. 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 ɑ-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 GBA1 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 α-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. |
| format | Article |
| id | doaj-art-6e8fda5c13944f35b1e0dedb7c20c5e3 |
| institution | DOAJ |
| issn | 1750-1326 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj-art-6e8fda5c13944f35b1e0dedb7c20c5e32025-08-20T03:01:00ZengBMCMolecular Neurodegeneration1750-13262025-02-0120111710.1186/s13024-025-00809-0From mechanisms to future therapy: a synopsis of isolated REM sleep behavior disorder as early synuclein-related diseaseAmbra Stefani0Elena Antelmi1Dario Arnaldi2Isabelle Arnulf3Emmanuel During4Birgit Högl5Michele M. T. Hu6Alex Iranzo7Russell Luke8John Peever9Ronald B. Postuma10Aleksandar Videnovic11Ziv Gan-Or12Medical University InnsbruckDIMI Department of Engineering and Medicine of Innovation, University of VeronaClinical Neurophysiology, IRCCS Ospedale Policlinico San MartinoSleep Clinic, Pitié-Salpêtrière Hospital, APHP - Sorbonne UniversityDepartment of Neurology, Icahn School of Medicine at Mount SinaiMedical University InnsbruckDivision of Neurology, Nuffield Department of Clinical Neurosciences, Oxford UniversitySleep Unit, Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, CIBERNED: CB06/05/0018-ISCIII, Universitat de Barcelona,Department of Cell and System Biology, University of TorontoDepartment of Cell and System Biology, University of TorontoDepartment of Neurology and Neurosurgery, McGill UniversityDepartment of Neurology, Massachusetts General Hospital, Harvard Medical SchoolDepartment of Neurology and Neurosurgery, McGill UniversityAbstract Parkinson disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy are synucleinopathies, characterized by neuronal loss, gliosis and the abnormal deposition of α-synuclein in vulnerable areas of the nervous system. 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 ɑ-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 GBA1 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 α-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.https://doi.org/10.1186/s13024-025-00809-0 |
| spellingShingle | Ambra Stefani Elena Antelmi Dario Arnaldi Isabelle Arnulf Emmanuel During Birgit Högl Michele M. T. Hu Alex Iranzo Russell Luke John Peever Ronald B. Postuma Aleksandar Videnovic Ziv Gan-Or From mechanisms to future therapy: a synopsis of isolated REM sleep behavior disorder as early synuclein-related disease Molecular Neurodegeneration |
| title | From mechanisms to future therapy: a synopsis of isolated REM sleep behavior disorder as early synuclein-related disease |
| title_full | From mechanisms to future therapy: a synopsis of isolated REM sleep behavior disorder as early synuclein-related disease |
| title_fullStr | From mechanisms to future therapy: a synopsis of isolated REM sleep behavior disorder as early synuclein-related disease |
| title_full_unstemmed | From mechanisms to future therapy: a synopsis of isolated REM sleep behavior disorder as early synuclein-related disease |
| title_short | From mechanisms to future therapy: a synopsis of isolated REM sleep behavior disorder as early synuclein-related disease |
| title_sort | from mechanisms to future therapy a synopsis of isolated rem sleep behavior disorder as early synuclein related disease |
| url | https://doi.org/10.1186/s13024-025-00809-0 |
| work_keys_str_mv | AT ambrastefani frommechanismstofuturetherapyasynopsisofisolatedremsleepbehaviordisorderasearlysynucleinrelateddisease AT elenaantelmi frommechanismstofuturetherapyasynopsisofisolatedremsleepbehaviordisorderasearlysynucleinrelateddisease AT darioarnaldi frommechanismstofuturetherapyasynopsisofisolatedremsleepbehaviordisorderasearlysynucleinrelateddisease AT isabellearnulf frommechanismstofuturetherapyasynopsisofisolatedremsleepbehaviordisorderasearlysynucleinrelateddisease AT emmanuelduring frommechanismstofuturetherapyasynopsisofisolatedremsleepbehaviordisorderasearlysynucleinrelateddisease AT birgithogl frommechanismstofuturetherapyasynopsisofisolatedremsleepbehaviordisorderasearlysynucleinrelateddisease AT michelemthu frommechanismstofuturetherapyasynopsisofisolatedremsleepbehaviordisorderasearlysynucleinrelateddisease AT alexiranzo frommechanismstofuturetherapyasynopsisofisolatedremsleepbehaviordisorderasearlysynucleinrelateddisease AT russellluke frommechanismstofuturetherapyasynopsisofisolatedremsleepbehaviordisorderasearlysynucleinrelateddisease AT johnpeever frommechanismstofuturetherapyasynopsisofisolatedremsleepbehaviordisorderasearlysynucleinrelateddisease AT ronaldbpostuma frommechanismstofuturetherapyasynopsisofisolatedremsleepbehaviordisorderasearlysynucleinrelateddisease AT aleksandarvidenovic frommechanismstofuturetherapyasynopsisofisolatedremsleepbehaviordisorderasearlysynucleinrelateddisease AT zivganor frommechanismstofuturetherapyasynopsisofisolatedremsleepbehaviordisorderasearlysynucleinrelateddisease |