{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T01:34:53Z","timestamp":1791509693232,"version":"4.3.4"},"reference-count":66,"publisher":"American Society for Clinical Investigation","issue":"8","license":[{"start":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T00:00:00Z","timestamp":1713139200000},"content-version":"vor","delay-in-days":53,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Agency, France","award":["ANR\u201016\u2010RHUS\u20100004"],"award-info":[{"award-number":["ANR\u201016\u2010RHUS\u20100004"]}]},{"name":"National Research Agency, France","award":["ANR-20-CE37-0020-02"],"award-info":[{"award-number":["ANR-20-CE37-0020-02"]}]},{"name":"National Research Agency, France","award":["ANR-22-CE17-0010-01"],"award-info":[{"award-number":["ANR-22-CE17-0010-01"]}]},{"name":"NIH, USA","award":["1RF1NS128963"],"award-info":[{"award-number":["1RF1NS128963"]}]},{"name":"NIH, USA","award":["R01-NS-110656"],"award-info":[{"award-number":["R01-NS-110656"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,15]]},"abstract":"<jats:p>\n                    Loss of arterial smooth muscle cells (SMCs) and abnormal accumulation of the extracellular domain of the NOTCH3 receptor (Notch3\n                    <jats:sup>ECD<\/jats:sup>\n                    ) are the 2 core features of CADASIL, a common cerebral small vessel disease caused by highly stereotyped dominant mutations in\n                    <jats:italic>NOTCH3<\/jats:italic>\n                    . Yet the relationship between NOTCH3 receptor activity, Notch3\n                    <jats:sup>ECD<\/jats:sup>\n                    accumulation, and arterial SMC loss has remained elusive, hampering the development of disease-modifying therapies. Using dedicated histopathological and multiscale imaging modalities, we could detect and quantify previously undetectable CADASIL-driven arterial SMC loss in the CNS of mice expressing the archetypal Arg169Cys mutation. We found that arterial pathology was more severe and Notch3\n                    <jats:sup>ECD<\/jats:sup>\n                    accumulation greater in transgenic mice overexpressing the mutation on a wild-type\n                    <jats:italic>Notch3<\/jats:italic>\n                    background (Tg\n                    <jats:italic>\n                      Notch3\n                      <jats:sup>R169C<\/jats:sup>\n                    <\/jats:italic>\n                    ) than in knockin\n                    <jats:italic>\n                      Notch3\n                      <jats:sup>R170C\/R170C<\/jats:sup>\n                    <\/jats:italic>\n                    mice expressing this mutation without a wild-type\n                    <jats:italic>Notch3<\/jats:italic>\n                    copy. Notably, expression of\n                    <jats:italic>Notch3<\/jats:italic>\n                    -regulated genes was essentially unchanged in Tg\n                    <jats:italic>\n                      Notch3\n                      <jats:sup>R169C<\/jats:sup>\n                    <\/jats:italic>\n                    arteries. We further showed that wild-type Notch3\n                    <jats:sup>ECD<\/jats:sup>\n                    coaggregated with mutant Notch3\n                    <jats:sup>ECD<\/jats:sup>\n                    and that elimination of 1 copy of wild-type\n                    <jats:italic>Notch3<\/jats:italic>\n                    in Tg\n                    <jats:italic>\n                      Notch3\n                      <jats:sup>R169C<\/jats:sup>\n                    <\/jats:italic>\n                    was sufficient to attenuate Notch3\n                    <jats:sup>ECD<\/jats:sup>\n                    accumulation and arterial pathology. These findings suggest that Notch3\n                    <jats:sup>ECD<\/jats:sup>\n                    accumulation, involving mutant and wild-type NOTCH3, is a major driver of arterial SMC loss in CADASIL, paving the way for NOTCH3-lowering therapeutic strategies.\n                  <\/jats:p>","DOI":"10.1172\/jci175789","type":"journal-article","created":{"date-parts":[[2024,2,22]],"date-time":"2024-02-22T12:00:27Z","timestamp":1708603227000},"source":"Crossref","is-referenced-by-count":41,"title":["Protein aggregates containing wild-type and mutant NOTCH3 are major drivers of arterial pathology in CADASIL"],"prefix":"10.1172","volume":"134","author":[{"given":"Nicolas","family":"Dupr\u00e9","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Paris, 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