Neuronal TNFα, not α-syn, underlies PDD-like disease progression in IFNβ-KO mice

Erika B Villanueva, Emilie Tresse, Yawei Liu, João N Duarte, Gisela Jimenez-Duran, Patrick Ejlerskov, Oliver Kretz, Desiree Loreth, Tobias Goldmann, Marco Prinz, Shohreh Issazadeh-Navikas

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

2 Citationer (Scopus)
65 Downloads (Pure)

Abstract

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. This article is protected by copyright. All rights reserved.

OriginalsprogEngelsk
TidsskriftAnnals of Neurology
Vol/bind90
Udgave nummer5
Sider (fra-til)789-807
ISSN0364-5134
DOI
StatusUdgivet - 2021

Emneord

  • Det Sundhedsvidenskabelige Fakultet
  • alpha-synuclein
  • amyloid-beta
  • interferon-beta
  • neuroinflammation
  • Parkinson's disease dementia
  • phosphorylated tau
  • tumor necrosis factor alpha

Citationsformater