Glia in amyotrophic lateral sclerosis and spinal cord injury: common therapeutic targets

Ban, Jelena; Sámano, Cynthia; Mladinić, Miranda; Munitić, Ivana

doi:10.3325/cmj.2019.60.109

Cited by 16 publications

(21 citation statements)

References 123 publications

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“…The proposed passive role of glia as the glue that holds neurons together, has been firmly abandoned ( Somjen, 1988 ; Ban et al , 2019 ). Glial cells actively maintain neuronal homeostasis but also take key roles in the neurodegenerative process ( Ransohoff, 2016 ).…”

Section: Glial Cells As Key Contributors To Als Pathogenesismentioning

confidence: 99%

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Béland

Markovinović

Jakovac

et al. 2020

Brain Communications

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Despite wide genetic, environmental and clinical heterogeneity in amyotrophic lateral sclerosis, a rapidly fatal neurodegenerative disease targeting motoneurons, neuroinflammation is a common finding. It is marked by local glial activation, T cell infiltration and systemic immune system activation. The immune system has a prominent role in the pathogenesis of various chronic diseases, hence some of them, including some types of cancer, are successfully targeted by immunotherapeutic approaches. However, various anti-inflammatory or immunosuppressive therapies in amyotrophic lateral sclerosis have failed. This prompted increased scrutiny over the immune-mediated processes underlying amyotrophic lateral sclerosis. Perhaps the biggest conundrum is that amyotrophic lateral sclerosis pathogenesis exhibits features of three otherwise distinct immune dysfunctions –excessive inflammation, autoimmunity and inefficient immune responses. Epidemiological and genome-wide association studies show only minimal overlap between amyotrophic lateral sclerosis and autoimmune diseases, so excessive inflammation is usually thought to be secondary to protein aggregation, mitochondrial damage or other stresses. In contrast, several recently characterized amyotrophic lateral sclerosis-linked mutations, including those in TBK1, OPTN, CYLD and C9orf72, could lead to inefficient immune responses and/or damage pile-up, suggesting that an innate immunodeficiency may also be a trigger and/or modifier of this disease. In such cases, nonselective immunosuppression would further restrict neuroprotective immune responses. Here we discuss multiple layers of immune-mediated neuroprotection and neurotoxicity in amyotrophic lateral sclerosis. Particular focus is placed on individual patient mutations that directly or indirectly affect the immune system, and the mechanisms by which these mutations influence disease progression. The topic of immunity in amyotrophic lateral sclerosis is timely and relevant, because it is one of the few common and potentially malleable denominators in this heterogenous disease. Importantly, amyotrophic lateral sclerosis progression has recently been intricately linked to patient T cell and monocyte profiles, as well as polymorphisms in cytokine and chemokine receptors. For this reason, precise patient stratification based on immunophenotyping will be crucial for efficient therapies.

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Section: Glial Cells As Key Contributors To Als Pathogenesismentioning

confidence: 99%

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Béland

Markovinović

Jakovac

et al. 2020

Brain Communications

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“…An extensive body of evidence has suggested that glia contribute to the neurodegeneration observed in ALS and FTD (9,10,(110)(111)(112)(113). Transcriptional assessments and proteomic approaches across the ALS/FTD spectrum have reported robust glia signatures and glia protein modules, respectively, emphasizing a glia involvement in inflammation and contribution to disease (109,(113)(114)(115).…”

Section: Discussionmentioning

confidence: 99%

Cellular and molecular phenotypes ofC9orf72ALS/FTD patient derived iPSC-microglia mono-cultures

Lorenzini

Alsop

Levy

et al. 2020

Preprint

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Background: A mutation in the C9orf72 gene is the most common genetic mutation of familial and sporadic ALS, as well as familial FTD. While prior studies have focused on elucidating the mechanisms of neuronal dysfunction and neurodegeneration associated with this genetic mutation, the contribution of microglia to disease pathogenesis in the ALS/FTD disease spectrum remains poorly understood. Methods: Here, we generated a new disease model consisting of cultured C9orf72 ALS/FTD patient-derived induced pluripotent stem cells differentiated into microglia (iPSC-MG). We used this model to study the intrinsic cellular and molecular phenotypes of microglia triggered by the C9orf72 gene mutation. Results: We show that C9orf72 ALS/FTD iPSC-MG have a similar transcriptional profile compared to control iPSC-MG, despite the presence of C9orf72-associated phenotypes including reduced C9orf72 protein levels and dipeptide-repeat protein translation. Interestingly, C9orf72 ALS/FTD iPSC-MG exhibit intrinsic dysfunction of phagocytic activity upon exposure to Aβ or brain synaptoneurosomes and display a heightened inflammatory response. Detailed analysis of the endosomal and lysosomal pathways revealed altered expression of endosomal marker early endosome antigen 1 and lysosomal associated membrane protein 1 in C9orf72 ALS/FTD iPSC-MG, which was confirmed in patient postmortem tissues. Conclusions: These findings demonstrate that unstimulated C9orf72 iPSC-MG mono-cultures share a largely similar transcriptome profile with control microglia, despite the presence of C9orf72 disease phenotypes. The dysfunction of the endosomal-lysosomal pathway as demonstrated by aberrant microglia phagocytosis and engulfment of cellular debris and brain pathogens suggests that disease-related microglia phenotypes are not intrinsic but instead require microglia to be activated. In summary, the C9orf72 iPSC-MG culture system provides a novel human disease model to study the role of microglia in C9orf72 ALS/FTD disease pathogenesis.

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“…Травма спинного мозга (ТСМ) -тяжелое патологическое состояние, сопровождающееся повреждением и гибелью клеток, кровоизлиянием, воспалением, оте ком тканей, ионным дисбалансом, утратой аксонов, демиелинизацией, активацией иммунных клеток, астроглиозом, реорганизацией сосудистой системы и нейронных цепей [106]. При повреждении спинного мозга и развитии патологических процессов резидентная микроглия быстро реагирует на изменения микроокружения высвобождением специфических цитокинов, лейкотриенов и простаглан динов [107].…”

Section: микроглия при травме спинного мозгаunclassified

“…Это органическое поражение ЦНС является наиболее распространенной патологией, приводящей к нарушению функционирования двигательных нейронов СМ у взрослых. Этиология БАС остается неизвестной, поскольку большинство случаев заболевания относятся к спорадической форме [106]. При БАС выявляется перифокальное воспаление вокруг мотонейронов и аксональная дегенерация, что сопровождается накоплением реактивных астроцитов, активированной микроглии и лимфоцитов [138].…”

Section: микроглия при заболеваниях спинного мозгаunclassified

“…Блокирование функций микроглиоцитов приводит к улучшению состояния мышей, несущих ген mSOD1 [141,142]. Установлено, что микроглия способна привлекать Т-клетки в очаг поражения СМ, причем на ранних стадиях преобладают регуляторные Т-клетки (Treg), в то время как на поздних стадиях их количество уменьшается и преобладают эффекторные Т-клетки [106].…”

Section: микроглия при заболеваниях спинного мозгаunclassified

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Spinal cord microglia in health and disease

Kolos

Коржевский

2020

Acta Naturae

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The review summarizes data of recent experimental studies on spinal microglia, the least explored cells of the spinal cord. It focuses on the origin and function of microglia in mammalian spinal cord embryogenesis. The main approaches to the classification of microgliocytes based on their structure, function, and immunophenotypic characteristics are analyzed. We discuss the results of studies conducted on experimental models of spinal cord diseases such as multiple sclerosis, amyotrophic lateral sclerosis, systemic inflammation, and some others, with special emphasis on the key role of microglia in the pathogenesis of these diseases. The review highlights the need to detect the new microglia-specific marker proteins expressed at all stages of ontogeny. New sensitive and selective microglial markers are necessary in order to improve identification of spinal cord microgliocytes in normal and pathological conditions. Possible morphometric methods to assess the functional activity of microglial cells are presented.

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Glia in amyotrophic lateral sclerosis and spinal cord injury: common therapeutic targets

Cited by 16 publications

References 123 publications

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Cellular and molecular phenotypes ofC9orf72ALS/FTD patient derived iPSC-microglia mono-cultures

Spinal cord microglia in health and disease

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