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As their role in coordinating organismal responses to both internal and external factors have increasingly come into focus, small non-coding RNAs have emerged as an essential component to disease etiology. Using Systemic RNA interference Defective (SID) mutants of the nematode\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    , deficient in gene silencing, we examined the potential consequences of dysfunctional epigenomic regulation in the context of Parkinson\u2019s disease (PD). Specifically, the loss of either the\n                    <jats:italic>sid-1<\/jats:italic>\n                    or\n                    <jats:italic>sid-3<\/jats:italic>\n                    genes, which encode a dsRNA transporter and an endocytic regulatory non-receptor tyrosine kinase, respectively, conferred neuroprotection to dopaminergic (DA) neurons in an established transgenic\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>elegans<\/jats:italic>\n                    strain wherein overexpression of human \u03b1-synuclein (\u03b1-syn) from a chromosomally integrated multicopy transgene causes neurodegeneration. We further show that knockout of a specific microRNA,\n                    <jats:italic>mir-2<\/jats:italic>\n                    , attenuates \u03b1-syn neurotoxicity; suggesting that the native targets of\n                    <jats:italic>mir-2<\/jats:italic>\n                    -dependent gene silencing represent putative neuroprotective modulators. In support of this, we demonstrated that RNAi knockdown of multiple\n                    <jats:italic>mir-2<\/jats:italic>\n                    targets enhanced \u03b1-syn-induced DA neurodegeneration. Moreover, we demonstrate that\n                    <jats:italic>mir-2<\/jats:italic>\n                    overexpression originating in the intestine can induce neurodegeneration of DA neurons, an effect that was reversed by pharmacological inhibition of SID-3 activity. Interestingly,\n                    <jats:italic>sid-1<\/jats:italic>\n                    mutants retained\n                    <jats:italic>mir-2<\/jats:italic>\n                    -induced enhancement of neurodegeneration. Transcriptomic analysis of \u03b1-syn animals with and without a\n                    <jats:italic>sid-1<\/jats:italic>\n                    mutation revealed 27 differentially expressed genes with human orthologs related to a variety of diseases, including PD. Among these was\n                    <jats:italic>pgp-8<\/jats:italic>\n                    , encoding a P-glycoprotein-related ABC transporter. Notably,\n                    <jats:italic>sid-1<\/jats:italic>\n                    ;\n                    <jats:italic>pgp-8<\/jats:italic>\n                    double mutants abolished the neurodegeneration resulting from intestinal\n                    <jats:italic>mir-2<\/jats:italic>\n                    overexpression. This research positions known regulators of small RNA-dependent gene silencing within a framework that facilitates mechanistic evaluation of epigenetic responses to exogenous and endogenous factors influencing DA neurodegeneration, revealing a path toward new targets for therapeutic intervention of PD.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1010115","type":"journal-article","created":{"date-parts":[[2022,8,19]],"date-time":"2022-08-19T13:47:28Z","timestamp":1660916848000},"page":"e1010115","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["Systemic RNA Interference Defective (SID) genes modulate dopaminergic neurodegeneration in C. elegans"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2959-7990","authenticated-orcid":true,"given":"Anthony L.","family":"Gaeta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Brucker","family":"Nourse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4887-5151","authenticated-orcid":true,"given":"Karolina","family":"Willicott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3601-635X","authenticated-orcid":true,"given":"Luke E.","family":"McKay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candice M.","family":"Keogh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5571-7346","authenticated-orcid":true,"given":"Kylie","family":"Peter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4543-8391","authenticated-orcid":true,"given":"Shannon N.","family":"Russell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4613-0815","authenticated-orcid":true,"given":"Shusei","family":"Hamamichi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4238-0326","authenticated-orcid":true,"given":"Laura A.","family":"Berkowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1580-6122","authenticated-orcid":true,"given":"Kim A.","family":"Caldwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy A.","family":"Caldwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,8,19]]},"reference":[{"key":"pgen.1010115.ref001","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S1097-2765(01)00340-9","article-title":"Common Themes in Mechanisms of Gene Silencing","volume":"8","author":"D. 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