Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology

Abstract

Inflammation is likely a key contributor to the pathogenesis of Parkinson’s disease (PD), a progressively debilitating neurodegenerative disease that is accompanied by a pathological accumulation of the α-synuclein protein in a staged manner through the brain. What leads to the accumulation of α-synuclein in PD and how this relates to inflammatory pathways, however, is not entirely clear. Toll-like receptor (TLR) signaling is a major pathway mediating inflammation and, in particular, TLR2 is increasingly being implicated in PD. We have, therefore, examined the expression of TLR2 in postmortem brain tissue from PD patients and matched controls. We confirm that TLR2 is increased in PD brain, and find that levels of TLR2 correlate with the accumulation of pathological α-synuclein. TLR2 was expressed on neurons as well as microglia; however, the neuronal rather than glial expression of TLR2 was significantly increased in PD brain in accordance with disease staging, and TLR2 was strongly localized to α-synuclein positive Lewy bodies. In cell culture, activation of neuronal TLR2 induced an inflammatory response, including the secretion of inflammatory cytokines and microglial-activating chemokines, as well as the production of reactive oxygen species. Moreover, activation of neuronal TLR2 increased levels of endogenous α-synuclein protein, which was in turn associated with increased levels of the autophagy/lysosomal pathway marker p62. Finally, promoting autophagy with rapamycin or pharmacological inhibition of the TLR2 signaling pathway prevented the TLR2-mediated increase in α-synuclein in neuronal cell cultures. These results implicate neuronal TLR2 expression in human PD pathogenesis. In particular, the increased expression of TLR2 on neurons may provide new insight into disease pathogenesis and/or options for therapeutic intervention.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1648-8) contains supplementary material, which is available to authorized users.

Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson’s disease pathogenesis

“…TLR4 also recruits a second signalling adaptor protein, TIR domain-containing adaptor-inducing interferon-beta (TRIF), via the TRIF-related adaptor molecule (TRAM). It is now clear that oligomeric proteins such as α-syn are recognised by TLRs 2 and 4 [6, 8, 13, 15, 25, 42, 54]. TLRs are also upregulated in the brains of patients with PD [12].…”

Glaucocalyxin B Alleviates Lipopolysaccharide-Induced Parkinson’s Disease by Inhibiting TLR/NF-κB and Activating Nrf2/HO-1 Pathway

“…In brain, TLRs are primarily expressed in immune cells such as microglia and astrocyte [27]. TLR4 is increased in 1-methyl-4-phenylpyridinium ion (MPP + )-induced PD model in vitro [28], and TLR2 is upregulated in the brain tissues of PD patients [29]. TLRs can be activated by LPS and inflammatory cytokines [30, 31], and they can further activate NF-κB via MyD88 and TNF receptor-associated factor 6-dependent pathway [32, 33].…”

Autophagy in neurodegenerative diseases: pathogenesis and therapy

“…Another study shows that decrease of immunophilin FKBP52 (FK506‐Binding Protein of MW ∼ 52 kDa), a protein co‐localized with lysosome, is accompanied with accumulation of neurofibrillary tangles . In postmortem brains of PD patients, expression of toll‐like receptor 2 (TLR2) is elevated in neurons and spatially correlated with the pathological α‐synuclein aggregation and increase of autophagy receptor SQSTM1 . Aberrant alternation of LAMP2, which is a significant marker in lysosome, is closely related with the early pathology of PD .…”