| Autor: |
Villanueva, Erika B., Tresse, Emilie, Liu, Yawei, Duarte, João N., Jimenez‐Duran, Gisela, Ejlerskov, Patrick, Kretz, Oliver, Loreth, Desiree, Goldmann, Tobias, Prinz, Marco, Issazadeh‐Navikas, Shohreh, Jimenez-Duran, Gisela, Issazadeh-Navikas, Shohreh |
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| Zdroj: |
Annals of Neurology; Nov2021, Vol. 90 Issue 5, p789-807, 19p |
| Abstrakt: |
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 (α-syn), a primary component of LBs, is implicated in PD pathogenesis, accumulating, and aggregating in both familial and sporadic PD. However, as α-syn pathology is often comorbid with amyloid-beta (Aβ) plaques and phosphorylated tau (pTau) tangles in PDD, it is still unclear whether α-syn is the primary cause of neurodegeneration in sporadic PDD. We aimed to determine how the absence of α-syn would affect PDD manifestation.Methods: IFN-β knockout (Ifnb-/- ) mice spontaneously develop progressive behavior abnormalities and neuropathology resembling PDD, notably with α-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-β loss. Independently of α-syn expression, lack of IFN-β alone induced Aβ plaques, pTau tangles, and LB-like Aβ+ /pTau+ inclusion bodies and neuroinflammation. IFN-β loss caused significant elevated glial and neuronal TNF-α and neuronal TNFR1, associated with neurodegeneration. Restoring neuronal IFN-β signaling or blocking TNFR1 rescued caspase 3/t-BID-mediated neuronal-death through upregulation of c-FLIPS and lowered intraneuronal Aβ and pTau accumulation.Interpretation: These findings increase our understanding of PD pathology and suggest that targeting α-syn alone is not sufficient to mitigate disease. Targeting specific aspects of neuroinflammation, such as aberrant neuronal TNF-α/TNFR1 or IFN-β/IFNAR signaling, may attenuate disease. ANN NEUROL 2021;90:789-807. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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