Neuronal TNFα, Not α-Syn, Underlies PDD-Like Disease Progression in IFNβ-KO Mice

Objective Parkinson's disease (PD) manifests in motor dysfunction, non-motor symptoms, and eventual dementia (PDD). Neuropathological hallmarks include nigrostriatal neurodegeneration, Lewy body (LB) pathology, and neuroinflammation. Alpha-synuclein (alpha-syn), a primary component of LBs, is implicated in PD pathogenesis, accumulating, and aggregating in both familial and sporadic PD. However, as alpha-syn pathology is often comorbid with amyloid-beta (A beta) plaques and phosphorylated tau (pTau) tangles in PDD, it is still unclear whether alpha-syn is the primary cause of neurodegeneration in sporadic PDD. We aimed to determine how the absence of alpha-syn would affect PDD manifestation. Methods IFN-beta knockout (Ifnb(-/-)) mice spontaneously develop progressive behavior abnormalities and neuropathology resembling PDD, notably with alpha-syn(+) LBs. We generated Ifnb/Snca double knockout (DKO) mice and evaluated their behavior and neuropathology compared with wild-type (Wt), Ifnb(-/-), and Snca(-/-) mice using immunohistochemistry, electron microscopy, immunoblots, qPCR, and modification of neuronal signaling. Results Ifnb/Snca DKO mice developed all clinical PDD-like behavioral manifestations induced by IFN-beta loss. Independently of alpha-syn expression, lack of IFN-beta alone induced A beta plaques, pTau tangles, and LB-like A beta(+)/pTau(+) inclusion bodies and neuroinflammation. IFN-beta loss caused significant elevated glial and neuronal TNF-alpha and neuronal TNFR1, associated with neurodegeneration. Restoring neuronal IFN-beta signaling or blocking TNFR1 rescued caspase 3/t-BID-mediated neuronal-death through upregulation of c-FLIPS and lowered intraneuronal A beta and pTau accumulation. Interpretation These findings increase our understanding of PD pathology and suggest that targeting alpha-syn alone is not sufficient to mitigate disease. Targeting specific aspects of neuroinflammation, such as aberrant neuronal TNF-alpha/TNFR1 or IFN-beta/IFNAR signaling, may attenuate disease. ANN NEUROL 2021

Automated summary

In sporadic PDD, targeting alpha-syn alone may not be sufficient to alleviate the disease. Targeting specific aspects of neuroinflammation, such as aberrant neuronal TNF-alpha/TNFR1 or IFN-beta/IFNAR signaling, may attenuate the disease.