Latent changes in trigeminal ganglion structure and function resembling inflammatory conditions may predispose to acute attacks of migraine pain. Here, we investigated whether, in trigeminal sensory ganglia, cytokines such as TNFα might contribute to a local inflammatory phenotype of a transgenic knock-in (KI) mouse model of familial hemiplegic migraine type-1 (FHM-1). To this end, macrophage occurrence and cytokine expression in trigeminal ganglia were compared between wild type (WT) and R192Q mutant CaV2.1 Ca2+ channel (R192Q KI) mice, a genetic model of FHM-1. Cellular and molecular characterization was performed using a combination of confocal immunohistochemistry and cytokine assays. With respect to WT, R192Q KI trigeminal ganglia were enriched in activated macrophages as suggested by their morphology and immunoreactivity to the markers Iba1, CD11b, and ED1. R192Q KI trigeminal ganglia constitutively expressed higher mRNA levels of IL1β, IL6, IL10 and TNFα cytokines and the MCP-1 chemokine. Consistent with the report that TNFα is a major factor to sensitize trigeminal ganglia, we observed that, following an inflammatory reaction evoked by LPS injection, TNFα expression and macrophage occurrence were significantly higher in R192Q KI ganglia with respect to WT ganglia. Our data suggest that, in KI trigeminal ganglia, the complex cellular and molecular environment could support a new tissue phenotype compatible with a neuroinflammatory profile. We propose that, in FHM patients, this condition might contribute to trigeminal pain pathophysiology through release of soluble mediators, including TNFα, that may modulate the crosstalk between sensory neurons and resident glia, underlying the process of neuronal sensitisation.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the Substantia Nigra and the formation of ubiquitin- and alpha-synuclein (aSYN)-positive cytoplasmic inclusions called Lewy bodies (LBs). Although most PD cases are sporadic, families with genetic mutations have been found. Mutations in PARK7/DJ-1 have been associated with autosomal recessive early-onset PD, while missense mutations or duplications of aSYN (PARK1, PARK4) have been linked to dominant forms of the disease. In this study, we identify the E3 ubiquitin ligase tumor necrosis factor-receptor associated factor 6 (TRAF6) as a common player in genetic and sporadic cases. TRAF6 binds misfolded mutant DJ-1 and aSYN. Both proteins are substrates of TRAF6 ligase activity in vivo. Interestingly, rather than conventional K63 assembly, TRAF6 promotes atypical ubiquitin linkage formation to both PD targets that share K6-, K27- and K29- mediated ubiquitination. Importantly, TRAF6 stimulates the accumulation of insoluble and polyubiquitinated mutant DJ-1 into cytoplasmic aggregates. In human post-mortem brains of PD patients, TRAF6 protein colocalizes with aSYN in LBs. These results reveal a novel role for TRAF6 and for atypical ubiquitination in PD pathogenesis.
Mutations in PARK7 DJ-1 have been associated with autosomal-recessive early-onset Parkinson's disease (PD). This gene encodes for an atypical peroxiredoxin-like peroxidase that may act as a regulator of transcription and a redox-dependent chaperone. Although large gene deletions have been associated with a loss-of-function phenotype, the pathogenic mechanism of several missense mutations is less clear. By performing a yeast two-hybrid screening from a human fetal brain library, we identified TRAF and TNF receptor-associated protein (TTRAP), an ubiquitin-binding domain-containing protein, as a novel DJ-1 interactor, which was able to bind the PD-associated mutations M26I and L166P more strongly than wild type. TTRAP protected neuroblastoma cells from apoptosis induced by proteasome impairment. In these conditions, endogenous TTRAP relocalized to a detergent-insoluble fraction and formed cytoplasmic aggresome-like structures. Interestingly, both DJ-1 mutants blocked the TTRAP protective activity unmasking a c-jun N-terminal kinase (JNK)-and p38-MAPK (mitogen-activated protein kinase)-mediated apoptosis. These results suggest an active role of DJ-1 missense mutants in the control of cell death and position TTRAP as a new player in the arena of neurodegeneration. Cell Death and Differentiation (2009) Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder, affecting 1-2% of all individuals above the age of 65 years. Its neuropathological hallmark is the selective degeneration of subsets of mesencephalic dopaminergic cells and the formation of proteinaceous cytoplasmic aggregates called Lewy bodies. 1 Several studies implicate the ubiquitin-proteasome system in PD pathogenesis. 2 Synthetic proteasome inhibitors preferentially affect catecholaminergic neurons, leading to cell death. Furthermore, key ubiquitin-proteasome system elements are altered in PD post-mortem brains. [3][4][5] The identification of genes (PARK1-14) associated with familial PD has provided crucial insights into the pathogenic mechanisms. 1 The ubiquitin ligase parkin (PARK2) and the ubiquitin C-terminal hydrolase-L1 (UCH-L1) (PARK5) have been implicated in the ubiquitin-proteasome system function. Interestingly, upon treatment with proteasome inhibitors, they formed insoluble aggregates and were recruited to a juxtanuclear aggresome-like inclusion that resembled the Lewy body. 6,7 Autosomal-recessive early-onset PD has been associated with mutations in PARK7/DJ-1. 8 Functional DJ-1 is a dimer that acts as an atypical peroxiredoxin-like peroxidase as well as a regulator of transcription and a chaperone. 9-12 Interestingly, ectopic DJ-1 expression protects cells from death induced by a variety of insults. 13 DJ-1 loss in humans causes PD. 14 DJ-1 knock-out (KO) mice and flies showed increased vulnerabilities to neurotoxic agents but no signs of dopaminergic cell death. [15][16][17] PD families may also present missense mutations of DJ-1 in homozygous (L166P, M26I and E64D) and heterozygous forms (A104T and D149A)....
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