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Historically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, PD pathology is now known to be widespread and to affect serotonin, cholinergic and norepinephrine neurons as well as nerve cells in the olfactory system, cerebral hemisphere, brain stem, spinal cord, and peripheral autonomic nervous system. PD pathology is characterized by the accumulation of misfolded \u03b1\u2010synuclein, which is thought to play a critical role in the etiopathogenesis of the disease. Animal models of PD suggest that activation of the Abelson tyrosine kinase (c\u2010Abl) plays an essential role in the initiation and progression of \u03b1\u2010synuclein pathology and neurodegeneration. These studies demonstrate that internalization of misfolded \u03b1\u2010synuclein activates c\u2010Abl, which phosphorylates \u03b1\u2010synuclein and promotes \u03b1\u2010synuclein pathology within the affected neurons. Additionally, c\u2010Abl inactivates parkin, disrupting mitochondrial quality control and biogenesis, promoting neurodegeneration. Post\u2010mortem studies of PD patients demonstrate increased levels of tyrosine phosphorylated \u03b1\u2010synuclein, consistent with the activation of c\u2010Abl in human disease. Although the c\u2010Abl inhibitor nilotinib failed to demonstrate clinical benefit in two double\u2010blind trials, novel c\u2010Abl inhibitors have been developed that accumulate in the brain and may inhibit c\u2010Abl at saturating levels. These novel inhibitors have demonstrated benefits in animal models of PD and have now entered clinical development. Here, we review the role of c\u2010Abl in the neurodegenerative disease process and consider the translational potential of c\u2010Abl inhibitors from model studies to disease\u2010modifying therapies for Parkinson's disease. \u00a9 2021 Inhibikase Therapeutics, Inc. <jats:italic>Movement Disorders<\/jats:italic> published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.<\/jats:p>","DOI":"10.1002\/mds.28858","type":"journal-article","created":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T02:47:38Z","timestamp":1637722058000},"page":"6-15","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Parkinson's Disease Modification Through Abl Kinase Inhibition: An Opportunity"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7091-3716","authenticated-orcid":false,"given":"Milton H.","family":"Werner","sequence":"first","affiliation":[{"name":"Inhibikase Therapeutics, Inc.  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