{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T06:04:16Z","timestamp":1780639456783,"version":"3.54.1"},"reference-count":139,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>The accumulation of aberrant proteins or their impaired clearance leads to neurodegenerative diseases (NDs). The protein amino terminus (Nt) and its modifications determine the fate of proteins and their cellular effects. Nt acetylation, Nt methylation, and Nt myristoylation are protein Nt modifications implicated in the pathogenesis of proteinopathies like Alzheimer\u2019s, Parkinson\u2019s, and Huntington\u2019s diseases by regulating the protein lifespan, folding, and interaction with protein\/DNA. In particular, Nt acetylation shields proteins from degradation or targets them for the same, thereby affecting their fate. Distinct enzymes catalyze Nt acetylation, Nt methylation, and Nt myristoylation, and these modifications compete for the nascent polypeptide at the ribosomal exit tunnel. Dysregulation of Nt modifications initiates the protein aggregation cascade and could potentially induce neuroinflammation and neurodegeneration. Here, we review Nt modifications and their emerging roles in the pathogenesis of NDs. Further, we highlight the crosstalk among distinct Nt modifications and explore how their convergence may shape disease vulnerability and progression.<\/jats:p>","DOI":"10.3389\/fnagi.2026.1809812","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T05:37:03Z","timestamp":1780637823000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["N-terminal modifications as fate switches in neurodegeneration: a mechanistic review"],"prefix":"10.3389","volume":"18","author":[{"given":"Disha","family":"Mukherjee","sequence":"first","affiliation":[{"name":"School of Bio Sciences and Technology, Vellore Institute of Technology","place":["Vellore, Tamil Nadu, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sampath","family":"Raghul Kannan","sequence":"additional","affiliation":[{"name":"School of Bio Sciences and Technology, Vellore Institute of Technology","place":["Vellore, Tamil Nadu, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramasamy","family":"Tamizhselvi","sequence":"additional","affiliation":[{"name":"School of Bio Sciences and Technology, Vellore Institute of Technology","place":["Vellore, Tamil Nadu, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1021\/acs.biochem.6b00936","article-title":"Proteins containing expanded polyglutamine tracts and neurodegenerative disease","volume":"56","author":"Adegbuyiro","year":"2017","journal-title":"Biochemistry"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"102538","DOI":"10.1016\/j.arr.2024.102538","article-title":"Small molecule modulators of alpha-synuclein aggregation and toxicity: pioneering an emerging arsenal against Parkinson\u2019s disease","volume":"101","author":"Ahanger","year":"2024","journal-title":"Ageing Res. 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