Upregulation of microglial C1q expression has no effects on nigrostriatal dopaminergic injury in the MPTP mouse model of Parkinson disease

Depboylu, Candan; Schorlemmer, Kathrin; Klietz, Martin; Oertel, Wolfgang H.; Weihe, Eberhard; Höglinger, Günter U.; Schäfer, Martin

doi:10.1016/j.jneuroim.2011.05.006

Cited by 37 publications

(31 citation statements)

References 47 publications

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“…However, our finding that suppression of C1q induction in ALS mice did not protect against motor neuron degeneration, nor against synaptic loss, rather suggests that any disease contribution of C1q induction is dependent on the precise neurodegnerative condition or neuronal systems implicated, and a proposed deleterious role, with respect to neuroinflammation and synaptic degeneration, cannot be easily generalized. Consistent with this idea, recent findings from Parkinson disease mouse models did not find protection against dopaminergic neurodegeneration after suppression of C1q induction (57).…”

Section: Discussionmentioning

confidence: 66%

C1q induction and global complement pathway activation do not contribute to ALS toxicity in mutant SOD1 mice

Lobsiger

Boillée

Pozniak³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Accumulating evidence from mice expressing ALS-causing mutations in superoxide dismutase (SOD1) has implicated pathological immune responses in motor neuron degeneration. This includes microglial activation, lymphocyte infiltration, and the induction of C1q, the initiating component of the classic complement system that is the protein-based arm of the innate immune response, in motor neurons of multiple ALS mouse models expressing dismutase active or inactive SOD1 mutants. Robust induction early in disease course is now identified for multiple complement components (including C1q, C4, and C3) in spinal cords of SOD1 mutantexpressing mice, consistent with initial intraneuronal C1q induction, followed by global activation of the complement pathway. We now test if this activation is a mechanistic contributor to disease. Deletion of the C1q gene in mice expressing an ALS-causing mutant in SOD1 to eliminate C1q induction, and complement cascade activation that follows from it, is demonstrated to produce changes in microglial morphology accompanied by enhanced loss, not retention, of synaptic densities during disease. C1q-dependent synaptic loss is shown to be especially prominent for cholinergic C-bouton nerve terminal input onto motor neurons in affected C1q-deleted SOD1 mutant mice. Nevertheless, overall onset and progression of disease are unaffected in C1q-and C3-deleted ALS mice, thus establishing that C1q induction and classic or alternative complement pathway activation do not contribute significantly to SOD1 mutant-mediated ALS pathogenesis in mice.amyotrophic lateral sclerosis | motoneuron | synaptic density | gender differences | neuroinflammation

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Section: Discussionmentioning

confidence: 66%

C1q induction and global complement pathway activation do not contribute to ALS toxicity in mutant SOD1 mice

Lobsiger

Boillée

Pozniak³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The specific actions of MPP + and MPTP in glial and microglial activation associated with inflammatory mediator production remain ambiguous [16] . In the brain, MPTP induces reactive gliosis, the cellular manifestation of neuroinflammation, as a common response to neuronal injury [17] .…”

Section: Discussionmentioning

confidence: 99%

6-Shogaol, an active compound of ginger, protects dopaminergic neurons in Parkinson's disease models via anti-neuroinflammation

Park

Kim

et al. 2013

Acta Pharmacol Sin

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Aim: 6-Shogaol [1-(4-hydroxy-methoxyphenyl)-4-decen-one], a pungent compound isolated from ginger, has shown various neurobiological and anti-inflammatory effects. The aim of this study was to examine the effects of 6-shogaol on neuroinflammatory-induced damage of dopaminergic (DA) neurons in Parkinson's disease (PD) models. Methods: Cultured rat mesencephalic cells were treated with 6-shogaol (0.001 and 0.01 μmol/L) for 1 h, then with MPP + (10 µmol/L) for another 23 h. The levels of TNF-α and NO in medium were analyzed spectrophotometrically. C57/BL mice were administered 6-shogaol (10 mg·kg -1 ·d -1 , po) for 3 d, and then MPTP (30 mg/kg, ip) for 5 d. Seven days after the last MPTP injection, behavioral testings were performed. The levels of tyrosine hydroxylase (TH) and macrophage antigen (MAC)-1 were determined with immunohistochemistry. The expression of iNOS and COX-2 was measured using RT PCR. Results: In MPP + -treated rat mesencephalic cultures, 6-shogaol significantly increased the number of TH-IR neurons and suppressed TNF-α and NO levels. In C57/BL mice, treatment with 6-shogaol reversed MPTP-induced changes in motor coordination and bradykinesia. Furthermore, 6-shogaol reversed MPTP-induced reductions in TH-positive cell number in the substantia nigra pars compacta (SNpc) and TH-IR fiber intensity in stratum (ST). Moreover, 6-shogaol significantly inhibited the MPTP-induced microglial activation and increases in the levels of TNF-α, NO, iNOS, and COX-2 in both SNpc and ST. Conclusion: 6-Shogaol exerts neuroprotective effects on DA neurons in in vitro and in vivo PD models.

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“…The following primary antibodies were used: sheep polyclonal anti-TH (AB1542; Chemicon International, Temecula, CA, USA; 1/500), rabbit polyclonal anti-serotonin transporter (SERT; 24330; ImmunoStar, Hudson, WI, USA; 1/2000), mouse monoclonal anti-delta isoform of oncogene FosB (DFosB; sc-48; Santa Cruz Biotechnology, Santa Cruz, CA, USA; 1/2000). Bound primary antibodies were visualized using biotinylated secondary antibodies from donkey (Dianova, Hamburg, Germany; 1/200), standard avidin-biotin-peroxidase techniques (Vectastain Elite ABC kit, Boehringer, Germany; 1/500), and finally with 3,3 0 -diaminobenzidine (Sigma-Aldrich) and nickel ammonium sulfate (Fluka, Buchs, Switzerland), resulting in a dark blue/black staining (Depboylu et al, 2011). Additionally, TH (1/500) was co-stained with neuronal nuclear antigen (NeuN; mouse monoclonal; MAB377; Chemicon International; 1/ 1000) by immunofluorescence using Cy3-and Alexa488-conjugated secondary antibodies (Dianova; 1/500), respectively.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Striatal tyrosine hydroxylase-positive neurons are associated with l-DOPA-induced dyskinesia in hemiparkinsonian mice

et al. 2015

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Upregulation of microglial C1q expression has no effects on nigrostriatal dopaminergic injury in the MPTP mouse model of Parkinson disease

Cited by 37 publications

References 47 publications

C1q induction and global complement pathway activation do not contribute to ALS toxicity in mutant SOD1 mice

C1q induction and global complement pathway activation do not contribute to ALS toxicity in mutant SOD1 mice

6-Shogaol, an active compound of ginger, protects dopaminergic neurons in Parkinson's disease models via anti-neuroinflammation

Striatal tyrosine hydroxylase-positive neurons are associated with l-DOPA-induced dyskinesia in hemiparkinsonian mice

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