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Efficacy of several antidiabetic drugs has been tested in PD. Exenatide, a synthetic version of exendin\u20104, an incretin\u2010mimetic drug, is an agonist of glucagon\u2010like peptide 1 receptor (GLP1R) and is approved for the treatment of T2DM. Exenatide can cross the blood\u2013brain barrier and exerts neuroprotective and neurorestorative effects via GLP1R at doses similar to those used in T2DM, resulting in improved motor performance, behaviour, learning and memory in different rodent PD models. Reports in human PD patients have also shown promise. In this work, we carried out substitution at the fourteenth position of exenatide (M14) with basic, acidic and nonpolar residues and investigated their effect on aggregation of recombinant human \u03b1\u2010synuclein\n                    <jats:italic>in vitro<\/jats:italic>\n                    and in SH\u2010SY5Y cells. Molecular dynamic (MD) simulation studies showed altered stability of \u03b1\u2010synuclein upon substitution at M14 in exenatide. Exenatide had no effect on aggregation of \u03b1\u2010synuclein\n                    <jats:italic>in vitro<\/jats:italic>\n                    . The M14K mutant, which stabilized \u03b1\u2010synuclein, prolonged lag time and caused significant reduction in aggregation. On the contrary, aggregation of \u03b1\u2010synuclein was significantly attenuated in SH\u2010SY5Y cells in the presence of exenatide for all mutants tested, with a concomitant increase in cell survival. Flow cytometric analysis suggested induction of autophagy in the presence of the peptides, explaining the reduction in protein aggregation. Thus, mutants of exenatide could be investigated further as inhibitors of aggregation of \u03b1\u2010synuclein.\n                  <\/jats:p>","DOI":"10.1111\/febs.70321","type":"journal-article","created":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T08:29:47Z","timestamp":1762676987000},"page":"1415-1432","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<scp>M14<\/scp>\n                    substitutions in exanatide modulate alpha\u2010synuclein aggregation"],"prefix":"10.1111","volume":"293","author":[{"given":"Venkataharsha","family":"Panuganti","sequence":"first","affiliation":[{"name":"Department of Biotechnology National Institute of Pharmaceutical Education and Research  S.A.S. 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