{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:06:41Z","timestamp":1792519601280,"version":"4.5.0"},"reference-count":89,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council","award":["NSTC-114-2313-B-030-001"],"award-info":[{"award-number":["NSTC-114-2313-B-030-001"]}]},{"award":["NSTC-114-2313-B-030-001"],"award-info":[{"award-number":["NSTC-114-2313-B-030-001"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]},{"name":"USA FJCU Alumni Foundation","award":["F630410"],"award-info":[{"award-number":["F630410"]}]},{"name":"Collaborative Research Project between FJUH and FJU","award":["CPL-202508003"],"award-info":[{"award-number":["CPL-202508003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) remains an intractable motor neuron (MN) disease with a growing patient population and few effective treatments. Here, we review how extracellular phosphoglycerate kinase 1 (ePgk1) improves neurite outgrowth of MNs (NOMN) and axonal growth, both in vitro and in vivo. Our group first elucidated a novel non-canonical function of ePgk1 as a cross-tissue mediator between nerve and muscle tissues. We then discovered that neural membranous Enolase 2 (Eno2) serves as a receptor of ligand ePgk1 and that ePgk1-Eno2 interaction suppresses the Rac1-GTP\/p-Pak1-T423\/p-P38-T180\/pMK2-T334\/p-Limk1-S323 axis, reducing p-Cofilin and promoting NOMN and axonal growth, finally suggesting that the 419th aspartic acid residue of Eno2 mediates this interaction. In a crucial preclinical step, we truncated two short 16-amino-acid derivatives from Pgk1, FD-1\/-2, each mediating neuroprotection comparable to that of full-length 417-amino-acid Pgk1 in ALS animal models, in terms of improvements of innervated neuromuscular junction, MN cell bodies, motor performance, and endpoint prolongation. In this context, we also discuss the opposite function driven by Eno1-plasminogen interaction and by Eno2-ePgk1 interaction; the latter results in unfavorable for tumorigenesis. Unlike intracellular Pgk1 roles, ePgk1 is an extracellular factor with anti-angiogenic properties, further positioning ePgk1 and its FD-1\/-2 as promising protein\/peptide drugs for ALS treatment.<\/jats:p>","DOI":"10.3390\/biom16060893","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:49:42Z","timestamp":1781743782000},"page":"893","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Extracellular Pgk1 or Its Derived Short Peptide Interacted with Membrane-Associated Enolase 2 Receptor: A Potential Therapy for ALS Motor Neuron Degeneration"],"prefix":"10.3390","volume":"16","author":[{"given":"Bing-Chang","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Life Science, Fu Jen Catholic University, New Taipei City 242062, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juey-Jen","family":"Hwang","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Internal Medicine, Fu Jen Catholic University Hospital, New Taipei City 243004, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huai-Jen","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Life Science, Fu Jen Catholic University, New Taipei City 242062, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/S0140-6736(10)61156-7","article-title":"Amyotrophic lateral sclerosis","volume":"377","author":"Kiernan","year":"2011","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/nn.3584","article-title":"State of play in amyotrophic lateral sclerosis genetics","volume":"17","author":"Renton","year":"2014","journal-title":"Nat. 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