{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T06:36:41Z","timestamp":1776753401867,"version":"3.51.2"},"reference-count":79,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Mutations in the\n                      <jats:italic>leucine-rich repeat kinase 2<\/jats:italic>\n                      (\n                      <jats:italic>LRRK2<\/jats:italic>\n                      ) gene cause late-onset, autosomal dominant Parkinson\u2019s disease (PD).\n                      <jats:italic>LRRK2<\/jats:italic>\n                      encodes a multi-domain protein containing a Roc GTPase domain and a serine\/threonine-directed protein kinase domain, with PD-linked mutations known to enhance LRRK2 kinase activity and neuronal toxicity. Our previous studies identified the Golgi protein, ADP-Ribosylation Factor GTPase-Activating Protein 1 (ArfGAP1), as a novel modifier of LRRK2-induced cellular toxicity, where it can serve as a GAP-like protein and a robust kinase substrate of LRRK2.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Here, we further explore the phosphorylation of ArfGAP1 by LRRK2 and its functional consequences.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      LRRK2 mediates the robust phosphorylation of ArfGAP1\n                      <jats:italic>in vitro<\/jats:italic>\n                      within its lipid-sensing ALPS2 motif at residues Ser284, Thr291, and Thr292. We mutated these three candidate phosphorylation sites, either alone or combined, to create hydrophobic phospho-null or charged phospho-mimicking versions of ArfGAP1. We find that modulating ArfGAP1 phosphorylation at these sites impairs its normal capacity to induce Golgi fragmentation upon overexpression in neural cells. Blocking phosphorylation impairs ArfGAP1-induced neurite outgrowth inhibition in primary neurons and protects against the pathogenic effects of PD-linked G2019S LRRK2. ArfGAP1 interactome analysis in neural cells identifies 114 putative interacting proteins with a proportion of these localized to mitochondria, including the outer membrane proteins Voltage-Dependent Anion Channel (VDAC) 1\u20133. An ArfGAP1 triple phospho-mimic mutant displays an increased interaction with mitochondrial VDACs owing to the redistribution of ArfGAP1 from the\n                      <jats:italic>cis<\/jats:italic>\n                      -Golgi to the cytoplasm. Mimicking ArfGAP1 phosphorylation also blocks the formation of Golgi-derived vesicles following mild ER stress.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Our data provides evidence for a complex functional interaction between LRRK2 and ArfGAP1 that serves to regulate ArfGAP1 subcellular localization, protein interactions, activity and neuronal integrity via LRRK2-mediated phosphorylation of its membrane-binding ALPS2 motif. Our findings support additional validation of ArfGAP1 as a putative therapeutic target for modulating\n                      <jats:italic>LRRK2<\/jats:italic>\n                      -linked PD.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnmol.2026.1786336","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T05:36:46Z","timestamp":1776749806000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["LRRK2 regulates ArfGAP1 membrane localization, activity and neuronal integrity via phosphorylation within its lipid-sensing ALPS2 motif"],"prefix":"10.3389","volume":"19","author":[{"given":"Md. Shariful","family":"Islam","sequence":"first","affiliation":[{"name":"Department of Neurodegenerative Science, Van Andel Institute","place":["Grand Rapids, MI, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentin","family":"C\u00f3ppola-Segovia","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Science, Van Andel Institute","place":["Grand Rapids, MI, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Musso","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neurodegenerative Research, Brain Mind Institute, Swiss Federal Institute of Technology (EPFL)","place":["Lausanne, Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darren J.","family":"Moore","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Science, Van Andel Institute","place":["Grand Rapids, MI, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2156","DOI":"10.1002\/mds.23265","article-title":"Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson\u2019s disease.","volume":"25","author":"Aasly","year":"2010","journal-title":"Mov. 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