Neuronal TNFα, not α-syn, underlies PDD-like disease progression in IFNβ-KO mice
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Neuronal TNFα, not α-syn, underlies PDD-like disease progression in IFNβ-KO mice. / 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.
In: Annals of Neurology, Vol. 90, No. 5, 2021, p. 789-807.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Neuronal TNFα, not α-syn, underlies PDD-like disease progression in IFNβ-KO mice
AU - Villanueva, Erika B
AU - Tresse, Emilie
AU - Liu, Yawei
AU - Duarte, João N
AU - Jimenez-Duran, Gisela
AU - Ejlerskov, Patrick
AU - Kretz, Oliver
AU - Loreth, Desiree
AU - Goldmann, Tobias
AU - Prinz, Marco
AU - Issazadeh-Navikas, Shohreh
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Faculty of Health and Medical Sciences
KW - alpha-synuclein
KW - amyloid-beta
KW - interferon-beta
KW - neuroinflammation
KW - Parkinson's disease dementia
KW - phosphorylated tau
KW - tumor necrosis factor alpha
KW - alpha-synuclein
KW - amyloid-beta
KW - interferon-beta
KW - neuroinflammation
KW - Parkinson's disease dementia
KW - phosphorylated tau
KW - tumor necrosis factor alpha
U2 - 10.1002/ana.26209
DO - 10.1002/ana.26209
M3 - Journal article
C2 - 34476836
VL - 90
SP - 789
EP - 807
JO - Annals of Neurology
JF - Annals of Neurology
SN - 0364-5134
IS - 5
ER -
ID: 279126834