Infectious agents and amyotrophic lateral sclerosis: another piece of the puzzle of motor neuron degeneration

Castanedo-Vazquez, David; Bosque-Varela, Pilar; Sainz-Pelayo, Arancha; Riancho, Javier

doi:10.1007/s00415-018-8919-3

Cited by 36 publications

(25 citation statements)

References 75 publications

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“…For this reason, chronic systemic LPS administration precipitates ALS symptoms in the mutant hSOD1 mouse model ( Nguyen et al , 2004 ). Viral infections have also been proposed as potential risk factors as several studies detected viral genome elements in ALS patients’ spinal cords, mainly belonging to enteroviruses ( Berger et al , 2000 ; Giraud et al , 2001 ; Xue et al , 2018 a ; Castanedo-Vazquez et al , 2019 ). Furthermore, a small fraction of patients infected with human immunodeficiency virus-1 (HIV-1) or human T cell leukaemia virus-1 (HTLV-1) progress to an ALS-like syndrome, which responds to antiretroviral therapy ( Alfahad and Nath, 2013 ).…”

Section: How Does Immunity Turn From Friend To Foe During Als?mentioning

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: How Does Immunity Turn From Friend To Foe During Als?mentioning

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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“…Nevertheless, the involvement of many possible causal/risk factors has been suggested. This includes (but not limited to) chemicals, metals, radiation/electromagnetic fields, physical activity, dietary habits, viruses, bacteria, prions, fungi, protein-related abnormalities, mitochondria-related pathology, glutamate excitotoxicity, higher energy expenditure than intake and progressive impairment of glucose metabolism, microtubule mediated deficits in axonal transport, reactive phenotypes in astrocytes and microglia, autoimmunity, and moderate to severe traumatic brain injury [3,[6][7][8][9][10][11][12][13][14]…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress, Neuroinflammation and Mitochondria in the Pathophysiology of Amyotrophic Lateral Sclerosis

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron (MN) disease. Its primary cause remains elusive, although a combination of different causal factors cannot be ruled out. There is no cure, and prognosis is poor. Most patients with ALS die due to disease-related complications, such as respiratory failure, within three years of diagnosis. While the underlying mechanisms are unclear, different cell types (microglia, astrocytes, macrophages and T cell subsets) appear to play key roles in the pathophysiology of the disease. Neuroinflammation and oxidative stress pave the way leading to neurodegeneration and MN death. ALS-associated mitochondrial dysfunction occurs at different levels, and these organelles are involved in the mechanism of MN death. Molecular and cellular interactions are presented here as a sequential cascade of events. Based on our present knowledge, the discussion leads to the idea that feasible therapeutic strategies should focus in interfering with the pathophysiology of the disease at different steps.

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“…The cause of ALS remains unknown, although a great effort has been done to find the molecular causes of ALS. Viruses have been proposed to be an environmental factor for ALS [32], such as HSV [21][22][23], however, we lack of evidence to confirm this association. Curiously enough, several genes associated with ALS [33], such as SQSTM1/P62 or TBK1, are involved in autophagy and innate immune response, two critical defense mechanisms used by neurons and glial cells to control HSV infections [34][35][36].…”

Section: Introductionmentioning

confidence: 72%

Analysis of ALS-related proteins during herpes simplex virus-2 latent infection

Cabrera

Rodriguez-Izquierdo

Jiménez

et al. 2020

J Neuroinflammation

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Background Genetics have provided hints on potential molecular pathways involved in neurodegenerative diseases (NDD). However, the number of cases caused exclusively by genetic alterations is low, suggesting an important contribution of environmental factors to NDDs. Among these factors, viruses like herpes simplex viruses (HSV-2), capable of establishing lifelong infections within the nervous system (NS), are being proposed to have a role in NDDs. Despite promising data, there is a significant lack of knowledge on this and an urgent need for more research. Methods We have set up a mouse model to study HSV latency and its associated neuroinflammation in the spinal cord. The goal of this model was to observe neuroinflammatory changes caused by HSV latent infections, and if those changes were similar to alterations observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients. Results In infected spinal cords, we have observed a strong leukocyte infiltration and a severe alteration of microglia close to motor neurons. We have also analyzed ALS-related proteins: we have not found changes in TDP-43 and Fus in neurons, but interestingly, we have found decreased protein levels of C9orf72, of which coding gene is severely altered in some familial forms of ALS and is critical for microglia homeostasis. Conclusions Latent infection of HSV in the spinal cord showed altered microglia and leukocyte infiltration. These inflammatory features resembled to those observed in the spinal cord of ALS patients. No changes mimicking ALS neuropathology, such as TDP-43 cytoplasmic inclusions, were found in infected spinal cords, but a decrease in protein levels of C9orf72 was observed. Then, further studies should be required to determine whether HSV-2 has a role in ALS.

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Infectious agents and amyotrophic lateral sclerosis: another piece of the puzzle of motor neuron degeneration

Cited by 36 publications

References 75 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

Oxidative Stress, Neuroinflammation and Mitochondria in the Pathophysiology of Amyotrophic Lateral Sclerosis

Analysis of ALS-related proteins during herpes simplex virus-2 latent infection

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