Lewy body
MhcI
inflammation
prion
synuclein
transmission
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
25 Jul 2022
25 Jul 2022
Historique:
received:
15
06
2022
revised:
17
07
2022
accepted:
19
07
2022
entrez:
28
7
2022
pubmed:
29
7
2022
medline:
30
7
2022
Statut:
epublish
Résumé
MHCII molecules, expressed by professional antigen-presenting cells (APCs) such as T cells and B cells, are hypothesized to play a key role in the response of cellular immunity to α-synuclein (α-syn). However, the role of cellular immunity in the neuroanatomic transmission of α-syn pre-formed fibrillar (PFF) seeds is undetermined. To illuminate whether cellular immunity influences the transmission of α-syn seeds from the periphery into the CNS, we injected preformed α-syn PFFs in the hindlimb of the Line M83 transgenic mouse model of synucleinopathy lacking MhcII. We showed that a complete deficiency in MhcII accelerated the appearance of seeded α-syn pathology and shortened the lifespan of the PFF-seeded M83 mice. To characterize whether B-cell and T-cell inherent MhcII function underlies this accelerated response to PFF seeding, we next injected α-syn PFFs in Rag1-/- mice which completely lacked these mature lymphocytes. There was no alteration in the lifespan or burden of endstage α-syn pathology in the PFF-seeded, Rag1-deficient M83+/- mice. Together, these results suggested that MhcII function on immune cells other than these classical APCs is potentially involved in the propagation of α-syn in this model of experimental synucleinopathy. We focused on microglia next, finding that while microglial burden was significantly upregulated in PFF-seeded, MhcII-deficient mice relative to controls, the microglial activation marker Cd68 was reduced in these mice, suggesting that these microglia were not responsive. Additional analysis of the CNS showed the early appearance of the neurotoxic astrocyte A1 signature and the induction of the Ifnγ-inducible anti-viral response mediated by MhcI in the MhcII-deficient, PFF-seeded mice. Overall, our data suggest that the loss of MhcII function leads to a dysfunctional response in non-classical APCs and that this response could potentially play a role in determining PFF-induced pathology. Collectively, our results identify the critical role of MhcII function in synucleinopathies induced by α-syn prion seeds.
Identifiants
pubmed: 35897751
pii: ijms23158175
doi: 10.3390/ijms23158175
pmc: PMC9332117
pii:
doi:
Substances chimiques
Homeodomain Proteins
0
alpha-Synuclein
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NINDS NIH HHS
ID : R21 NS099738
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG061892
Pays : United States
Organisme : NIH HHS
ID : NS099738
Pays : United States
Organisme : NIH HHS
ID : T32 AG061892
Pays : United States
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