Mutant SOD1-expressing astrocytes release toxic factors that trigger motoneuron death by inducing hyperexcitability

Fritz, Elsa; Izaurieta, Pamela; Weiss, Alexandra; Mir, Franco Rafael; Rojas, Patricio; Gonzalez, David J.; Rojas, Fabiola; Brown, Robert H.; Madrid, Rodolfo; Zundert, Brigitte van

doi:10.1152/jn.00500.2012

Cited by 95 publications

(124 citation statements)

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“…This suggests that at least some of the detrimental effects seen with C3aR inhibition could be due to the lack of C3a-mediated reduction of astrocytes and microglia in this mouse model of ALS. This supports many studies where they have shown non-neuronal neighbouring cells (astrocytes and microglia) release toxic factors that are detrimental to motor neuron survival (Julien, 2007, Henkel et al, 2009, Fritz et al, 2013, Rojas et al, 2014. Although we showed increased microglia mRNA levels (Entpd1) in hSOD1 G93A x C3aR -/-mice when compared to hSOD1 G93A mice at midsymptomatic stage, we also showed a decrease in monocyte mRNA level (Ly6C) in hSOD1 G93A x C3aR -/-mice at the same age.…”

Section: 35supporting

confidence: 91%

The role of complement system in amyotrophic lateral sclerosis

Lee¹

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There is increasing evidence that neuro-inflammation drives disease progression in many neurodegenerative conditions. Amyotrophic lateral sclerosis (ALS) is a debilitating, late onset neurodegenerative disorder that is characterized by the progressive death of upper and α-motor neurons within the central nervous system (CNS). Components of the innate immune complement system have been implicated in the pathogenesis of ALS. Within the complement signalling cascade C3a and C5a are regarded as potent inflammatory and immunomodulatory peptides with various biological functions. In the CNS their functions include chemotaxis and proliferation of microglia and astrocytes; generation of superoxide radicals; and induction of pro-inflammatory cytokine synthesis -all thought to be achieved via their main signalling receptors C3aR and CD88. Some of these functions have been observed in neurodegenerative disease, suggesting that these complement factors may play a role in ALS pathogenesis. However a comprehensive examination of complement expression and function of C3aR and CD88 in this disease has not been performed.The initial aim of this thesis was to determine the expression of complement components (C1qB, C4, factor B, C3/C3b, C5, CD88 and C3aR) and regulators (CD55 and CD59a) in the lumbar spinal cord of the transgenic hSOD1 G93A mouse model of ALS. This was conducted during distinct disease stages, which were defined in this thesis. We found several early complement factors increased as disease progressed, whilst complement regulators decreased; suggesting overall increased complement activation through the classical or alternative pathways in hSOD1 G93A mice. CD88 and C3aR was also increased during disease progression, with immunolocalization demonstrating expression on motor neurons and increasing expression of CD88 on microglia and increasing expression of C3aR on astrocytes surrounding the regions of motor neuron death.Our previous studies have demonstrated that hSOD1 G93A rats treated with the selective CD88 antagonist PMX205 had reduced gliosis and improvements in behavioural deficits, consistent with reduced neuropathology; suggesting CD88 has a pathogenic function in ALS. However, the contribution of C3aR to disease progression in ALS is still unknown. This thesis therefore next aimed to confirm the function of CD88, and determine the function of C3aR, in the disease progression of ALS in hSOD1 G93A mice. The function of CD88 signalling was investigated using two different approaches (pharmacological and genetic). Inhibition of CD88 using PMX205 (pharmacological approach) or hSOD1 G93A mice lacking CD88 (genetic approach) showed similarly extended survival when compared to vehicle and hSOD1 G93A mice. There was also a reduction in microglia, monocytes and cytokines (TNFα and IL-1β) transcripts in the spinal cord at the end-stage of disease. Taken together these results indicate that inhibition of CD88 significantly attenuates III disease progression potentially by reducing microglia/monocyte activation...

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Section: 35supporting

confidence: 91%

The role of complement system in amyotrophic lateral sclerosis

Lee¹

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“…6,7 Muscle cramps occur in most patients with ALS during the course of the disease 13 and frequently cause distress. 14 Mexiletine, a cardiac antiarrhythmic agent and use-dependent sodium channel blocker, has recently been demonstrated to inhibit neuronal hyperexcitability and prevent cell death in a motor neuron cell line exposed to cultured media from astrocytes engineered to express the human SOD1 gene 15,16 and could potentially benefit patients with ALS.…”

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confidence: 99%

A randomized trial of mexiletine in ALS

et al. 2016

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Objective: To determine the safety and tolerability of mexiletine in a phase II double-blind randomized controlled trial of sporadic amyotrophic lateral sclerosis (SALS).Methods: Sixty participants with SALS from 10 centers were randomized 1:1:1 to placebo, mexiletine 300 mg/d, or mexiletine 900 mg/d and followed for 12 weeks. The primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetic study from plasma and CSF, ALS Functional Rating Scale-Revised (ALSFRS-R) score, slow vital capacity (SVC), and muscle cramp frequency and severity.Results: The only serious adverse event among active arm participants was one episode of imbalance. Thirty-two percent of participants receiving 900 mg of mexiletine discontinued study drug vs 5% on placebo (p 5 0.026). Pharmacokinetic study demonstrated a peak plasma concentration 2 hours postdose and strong correlation between plasma and CSF (p , 0.001). Rates of decline of ALSFRS-R and SVC did not differ from placebo. Analysis of all randomized patients demonstrated significant reductions of muscle cramp frequency (300 mg: rate 5 31% of placebo, p 5 0.047; 900 mg: 16% of placebo, p 5 0.002) and cramp intensity (300 mg: mean 5 45% of placebo, p 5 0.08; 900 mg: 25% of placebo, p 5 0.005). Conclusions:Mexiletine was safe at both doses and well-tolerated at 300 mg/d but adverse effects at 900 mg/d led to a high rate of discontinuation. Mexiletine treatment resulted in large dose-dependent reductions in muscle cramp frequency and severity. No effect on rate of progression was detected, but clinically important differences could not be excluded in this small and short-duration study. Classification of evidence:This study provides Class I evidence that mexiletine is safe when given daily to patients with amyotrophic lateral sclerosis at 300 and 900 mg and well-tolerated at the lower dose. Neurology ® 2016;86:1474-1481 GLOSSARY AE 5 adverse event; ALS 5 amyotrophic lateral sclerosis; ALSFRS-R 5 revised ALS Functional Rating Scale; AUC 5 area under the concentration curve; DSMB 5 data safety monitoring board; SAE 5 serious adverse event; SALS 5 sporadic amyotrophic lateral sclerosis; SF-36 5 Short Form-36 Health Survey; SVC 5 slow vital capacity.Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by death of cortical, brainstem, and spinal motor neurons. Riluzole, the sole Food and Drug Administration-approved therapy for ALS, has only a limited effect on slowing progression. 1 Recent in vivo 2-5 and in vitro 6-12 studies support a role for hyperexcitability of both peripheral motor nerve axons and cortical motor neurons as a possible pathogenic mechanism of ALS. Additionally, cortical motor neuronal hyperexcitability has been demonstrated in patients with

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“…Panel c is an equivalent relationship for the dependence of firing frequency on the voltage dependence of Na v channel activation Most recently, in vitro studies have also shown hyperexcitability of cultured iPSC-derived motor neurons from individuals with SOD1, FUS, and C9orf72 gene mutations [7,8]. The mechanisms whereby neurons in ALS may become hyperexcitable are multiple, with data implicating both endogenous membrane changes as well as excessively excitatory synaptic inputs [10,42,43] and excitatory stimuli from an astrocyte conditioned medium [9]. However, as indicated above, recent data have raised the important possibility that early motor neuronal hypoexcitability may be pivotal in ALS and other neurodegenerative disorders, initiating a cascade of events that compromise neuronal viability with hyperexcitability as a compensatory rather than a primary phenomenon [13,14].…”

Section: Discussionmentioning

confidence: 99%

“…Also evident, both in vivo and in vitro, are data implicating altered neuronal excitability as another key component of the pathophysiology of ALS. Neuronal hyperexcitability has been documented in primary spinal motor neuron cultures [5,6], in ALS motor neurons derived from induced pluripotential stem cells [7,8] and in slice preparations from transgenic mice carrying the familial ALS mutation G93A (hSOD1 G93A ) [9,10]. In the latter instance, the ALS mice exhibited augmented neuronal excitability and increased persistent sodium current [11].…”

Section: Introductionmentioning

confidence: 99%

“…In the latter instance, the ALS mice exhibited augmented neuronal excitability and increased persistent sodium current [11]. The hyperexcitability reflects at least three factors: intrinsic hyperexcitability of the neurons themselves, excessive excitatory inputs from interneurons [10], and pro-excitatory effects of soluble factors secreted by astrocytes [9]. Hypoexcitability has also been observed in iPSC-derived ALS motor neurons [12] and is also proposed to be a critical element in the early vulnerability of selected neuronal populations in ALS [13,14].…”

Section: Introductionmentioning

confidence: 99%

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Mutant SOD1 protein increases Nav1.3 channel excitability

et al. 2016

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Amyotrophic lateral sclerosis (ALS) is a lethal paralytic disease caused by the degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Mutations in the gene encoding copper/zinc superoxide dismutase (SOD1) are present in~20% of familial ALS and 2% of all ALS cases. The most common SOD1 gene mutation in North America is a missense mutation substituting valine for alanine (A4V). In this study, we analyze sodium channel currents in oocytes expressing either wild-type or mutant (A4V) SOD1 protein. We demonstrate that the A4V mutation confers a propensity to hyperexcitability on a voltage-dependent sodium channel (Na v 1.3) mediated by heightened total Na + conductance and a hyperpolarizing shift in the voltage dependence of Na v 1.3 activation. To estimate the impact of these channel effects on excitability in an intact neuron, we simulated these changes in the program NEURON; this shows that the changes induced by mutant SOD1 increase the spontaneous firing frequency of the simulated neuron. These findings are consistent with the view that excessive excitability of neurons is one component in the pathogenesis of this disease.

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Mutant SOD1-expressing astrocytes release toxic factors that trigger motoneuron death by inducing hyperexcitability

Abstract: . Mutant SOD1-expressing astrocytes release toxic factors that trigger motoneuron death by inducing hyperexcitability.

Cited by 95 publications

References 61 publications

The role of complement system in amyotrophic lateral sclerosis

The role of complement system in amyotrophic lateral sclerosis

A randomized trial of mexiletine in ALS

Mutant SOD1 protein increases Nav1.3 channel excitability

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