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Mol. Life Sci."],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Lewy body diseases (LBD) comprise a group of complex neurodegenerative conditions originating from accumulation of misfolded alpha-synuclein (\u03b1-syn) in the form of Lewy bodies. LBD pathologies are characterized by \u03b1-syn deposition in association with other proteins such as Amyloid \u03b2 (A\u03b2), Tau, and TAR-DNA-binding protein. To investigate the complex interactions of these proteins, we constructed 2 novel transgenic overexpressing (OE) <jats:italic>C. elegans<\/jats:italic> strains (\u03b1-syn<jats:sub>A53T<\/jats:sub>;Tau<jats:sub>pro-agg<\/jats:sub> (OE) and \u03b1-syn<jats:sub>A53T<\/jats:sub>;A\u03b21-42;Tau<jats:sub>pro-agg<\/jats:sub> (OE)) and compared them with previously established Parkinson\u2019s, Alzheimer\u2019s, and Lewy Body Dementia disease models. The LBD models presented here demonstrate impairments including uncoordinated movement, egg-laying deficits, altered serotonergic and cholinergic signaling, memory and posture deficits, as well as dopaminergic neuron damage and loss. Expression levels of total and prone to aggregation \u03b1-syn protein were increased in \u03b1-syn<jats:sub>A53T<\/jats:sub>;A\u03b2<jats:sub>1-42<\/jats:sub> but decreased in \u03b1-syn<jats:sub>A53T<\/jats:sub>;Tau<jats:sub>pro-agg<\/jats:sub> animals when compared to \u03b1-syn<jats:sub>A53T<\/jats:sub> animals suggesting protein interactions. These alterations were also observed at the mRNA level suggesting a pre-transcriptional mechanism. miRNA-seq revealed that <jats:italic>cel-miR-1018<\/jats:italic> was upregulated in LBD models \u03b1-syn<jats:sub>A53T<\/jats:sub>, \u03b1-syn<jats:sub>A53T<\/jats:sub>;A\u03b2<jats:sub>1-42<\/jats:sub>, and \u03b1-syn<jats:sub>A53T<\/jats:sub>;Tau<jats:sub>pro-agg<\/jats:sub> compared with WT. <jats:italic>cel-miR-58c<\/jats:italic> was upregulated in \u03b1-syn<jats:sub>A53T<\/jats:sub>;Tau<jats:sub>pro-agg<\/jats:sub> but downregulated in \u03b1-syn<jats:sub>A53T<\/jats:sub> and \u03b1-syn<jats:sub>A53T<\/jats:sub>;A\u03b2<jats:sub>1-42<\/jats:sub> compared with WT. <jats:italic>cel-miR-41-3p<\/jats:italic> and <jats:italic>cel-miR-355-5p<\/jats:italic> were significantly downregulated in 3 LBD models. Our results obtained in a model organism provide evidence of interactions between different pathological proteins and alterations in specific miRNAs that may further exacerbate or ameliorate LBD pathology.<\/jats:p>","DOI":"10.1007\/s00018-024-05383-0","type":"journal-article","created":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T15:02:06Z","timestamp":1725030126000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Novel C. elegans models of Lewy body disease reveal pathological protein interactions and widespread miRNA dysregulation"],"prefix":"10.1007","volume":"81","author":[{"given":"Rongzhen","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaobing","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linjing","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianjiao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ning","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangqing","family":"Hou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4566-9958","authenticated-orcid":false,"given":"Garry","family":"Wong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,8,30]]},"reference":[{"key":"5383_CR1","doi-asserted-by":"crossref","unstructured":"Obeso JA, Stamelou M, Goetz CG, Poewe W, Lang AE, Weintraub D, Burn D et al (2017) Past, present, and future of Parkinson\u2019s disease: a special essay on the 200th Anniversary of the Shaking Palsy. 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