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Alpha\u2010synuclein (\u03b1\u2010syn), a primary component of LBs, is implicated in PD pathogenesis, accumulating, and aggregating in both familial and sporadic PD. However, as \u03b1\u2010syn pathology is often comorbid with amyloid\u2010beta (A\u03b2) plaques and phosphorylated tau (pTau) tangles in PDD, it is still unclear whether \u03b1\u2010syn is the primary cause of neurodegeneration in sporadic PDD. We aimed to determine how the absence of \u03b1\u2010syn would affect PDD manifestation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>IFN\u2010\u03b2 knockout (<jats:italic>Ifnb<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>) mice spontaneously develop progressive behavior abnormalities and neuropathology resembling PDD, notably with \u03b1\u2010syn<jats:sup>+<\/jats:sup> LBs. We generated <jats:italic>Ifnb\/Snca<\/jats:italic> double knockout (DKO) mice and evaluated their behavior and neuropathology compared with wild\u2010type (Wt), <jats:italic>Ifnb<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>, and <jats:italic>Snca<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice using immunohistochemistry, electron microscopy, immunoblots, qPCR, and modification of neuronal signaling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Ifnb\/Snca<\/jats:italic> DKO mice developed all clinical PDD\u2010like behavioral manifestations induced by IFN\u2010\u03b2 loss. Independently of \u03b1\u2010syn expression, lack of IFN\u2010\u03b2 alone induced A\u03b2 plaques, pTau tangles, and LB\u2010like A\u03b2<jats:sup>+<\/jats:sup>\/pTau<jats:sup>+<\/jats:sup> inclusion bodies and neuroinflammation. IFN\u2010\u03b2 loss caused significant elevated glial and neuronal TNF\u2010\u03b1 and neuronal TNFR1, associated with neurodegeneration. Restoring neuronal IFN\u2010\u03b2 signaling or blocking TNFR1 rescued caspase 3\/t\u2010BID\u2010mediated neuronal\u2010death through upregulation of c\u2010FLIP<jats:sub>S<\/jats:sub> and lowered intraneuronal A\u03b2 and pTau accumulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>These findings increase our understanding of PD pathology and suggest that targeting \u03b1\u2010syn alone is not sufficient to mitigate disease. Targeting specific aspects of neuroinflammation, such as aberrant neuronal TNF\u2010\u03b1\/TNFR1 or IFN\u2010\u03b2\/IFNAR signaling, may attenuate disease. ANN NEUROL 2021;90:789\u2013807<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.26209","type":"journal-article","created":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T04:18:03Z","timestamp":1630642683000},"page":"789-807","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Neuronal <scp>TNF\u03b1<\/scp>, Not \u03b1\u2010Syn, Underlies <scp>PDD<\/scp>\u2010Like Disease Progression in <scp>IFN\u03b2\u2010KO<\/scp> Mice"],"prefix":"10.1002","volume":"90","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2270-3383","authenticated-orcid":false,"given":"Erika B.","family":"Villanueva","sequence":"first","affiliation":[{"name":"Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Tresse","sequence":"additional","affiliation":[{"name":"Biotech Research and Innovation 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