{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:35:29Z","timestamp":1785760529301,"version":"3.56.0"},"reference-count":47,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T00:00:00Z","timestamp":1753142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH NIEHS","award":["ES031124"],"award-info":[{"award-number":["ES031124"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>ATP13A2 is a lysosomal polyamine transporter with loss of function mutations linked to multiple neurodegenerative disorders including Parkinson\u2019s disease (PD). Knockout of ATP13A2 in mice leads to age-related sensorimotor impairments and in the brain lipofuscinosis, gliosis, and modest alpha-synuclein (\u03b1Syn) pathology. However, few studies have included ATP13A2 heterozygous mice as a comparison. In the present study, the effect of reduced or complete loss of ATP13A2 function on behavior, \u03b1Syn, gliosis, dopamine, and polyamines were determined in mice. Male and female ATP13A2 wildtype (WT), heterozygous (Het), and knockout (KO) mice were assessed behaviorally at 3, 12, and 18 months of age. In the brain, \u03b1Syn, phosphorylated \u03b1Syn, and GFAP were measured in the prefrontal cortex, striatum, ventral midbrain, and cerebellum. Polyamine and neurotransmitter analyses were performed in the same brain regions. Similar to previous studies, KO mice developed motor impairments and widespread gliosis in the brain. In addition, polyamine content was altered in Het and KO mice. In contrast, Het mice showed impairments in cognitive function and an age-related increase in \u03b1Syn in the brain. These results indicate potentially different pathological mechanisms when ATP13A2 is reduced compared to when it is knocked out and may have important implications for disease modification in synucleinopathies including PD.<\/jats:p>","DOI":"10.3390\/ijms26157030","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T08:45:18Z","timestamp":1753173918000},"page":"7030","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Phenotype Differences Between ATP13A2 Heterozygous and Knockout Mice Across Aging"],"prefix":"10.3390","volume":"26","author":[{"given":"Kristina","family":"Croucher","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2463-3657","authenticated-orcid":false,"given":"Josephine K.","family":"Lepp","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Bechtold","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward J.","family":"Hamad","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Scott","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Bittner","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Rogers","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Ong","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon","family":"Boehme","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinwen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila M.","family":"Fleming","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.bbrc.2004.08.156","article-title":"Characterization of the P5 subfamily of P-type transport ATPases in mice","volume":"323","author":"Schultheis","year":"2004","journal-title":"Biochem. 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