{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:07Z","timestamp":1787028427340,"version":"build-2736575974"},"reference-count":66,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,5,12]],"date-time":"2020-05-12T00:00:00Z","timestamp":1589241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glia cells are involved in upper motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Protease activated receptor 1 (PAR1) pathway is related to brain pathologies. Brain PAR1 is located on peri-synaptic astrocytes, adjacent to pyramidal motor neurons, suggesting possible involvement in ALS. Brain thrombin activity in superoxide dismutase 1 (SOD1) mice was measured using a fluorometric assay, and PAR1 levels by western blot. PAR1 was localized using immunohistochemistry staining. Treatment targeted PAR1 pathway on three levels; thrombin inhibitor TLCK (N-Tosyl-Lys-chloromethylketone), PAR1 antagonist SCH-79797 and the Ras intracellular inhibitor FTS (S-trans-trans-farnesylthiosalicylic acid). Mice were weighed and assessed for motor function and survival. SOD1 brain thrombin activity was increased (p &lt; 0.001) particularly in the posterior frontal lobe (p = 0.027) and hindbrain (p &lt; 0.01). PAR1 levels were decreased (p &lt; 0.001, brain, spinal cord, p &lt; 0.05). PAR1 and glial fibrillary acidic protein (GFAP) staining decreased in the cerebellum and cortex. SOD1 mice lost weight (\u226517 weeks, p = 0.047), and showed shorter rotarod time (\u226514 weeks, p &lt; 0.01). FTS 40mg\/kg significantly improved rotarod scores (p &lt; 0.001). Survival improved with all treatments (p &lt; 0.01 for all treatments). PAR1 antagonism was the most efficient, with a median survival improvement of 10 days (p &lt; 0.0001). Our results support PAR1 pathway involvement in ALS.<\/jats:p>","DOI":"10.3390\/ijms21103419","type":"journal-article","created":{"date-parts":[[2020,5,12]],"date-time":"2020-05-12T10:53:55Z","timestamp":1589280835000},"page":"3419","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Brain Protease Activated Receptor 1 Pathway: A Therapeutic Target in the Superoxide Dismutase 1 (SOD1) Mouse Model of Amyotrophic Lateral Sclerosis"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3373-8397","authenticated-orcid":false,"given":"Efrat","family":"Shavit-Stein","sequence":"first","affiliation":[{"name":"Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan 52626202, Israel"},{"name":"Department of Neurology and Neurosurgery, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ihab","family":"Abu Rahal","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan 52626202, Israel"},{"name":"Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doron","family":"Bushi","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan 52626202, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orna","family":"Gera","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan 52626202, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2452-8921","authenticated-orcid":false,"given":"Roni","family":"Sharon","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan 52626202, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6104-606X","authenticated-orcid":false,"given":"Shany G.","family":"Gofrit","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan 52626202, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea","family":"Pollak","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan 52626202, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Mindel","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Maggio","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan 52626202, Israel"},{"name":"Department of Neurology and Neurosurgery, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoel","family":"Kloog","sequence":"additional","affiliation":[{"name":"Department of Neurobiochemistry, Weiss Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joab","family":"Chapman","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan 52626202, Israel"},{"name":"Department of Neurology and Neurosurgery, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"Robert and Martha Harden Chair in Mental and Neurological Diseases, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4633-1481","authenticated-orcid":false,"given":"Amir","family":"Dori","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan 52626202, Israel"},{"name":"Department of Neurology and Neurosurgery, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, 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