Down-regulation of purinergic P2X7 receptor expression and intracellular calcium dysregulation in peripheral blood mononuclear cells of patients with amyotrophic lateral sclerosis

Liu, Jingyu; Prell, Tino; Stubendorff, Beatrice; Keiner, Silke; Ringer, Thomas; Gunkel, A.; Tadić, Vedrana; Goldhammer, Nadine; Malci, Ayse; Witte, Otto W.; Großkreutz, Julian

doi:10.1016/j.neulet.2016.07.039

Cited by 30 publications

(16 citation statements)

References 32 publications

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“…ALS is a multisystemic disease, in which pathological processes extend beyond the CNS [38]. In particular, PBMCs from ALS patients were reported to display to display traits of the disease including oxidative stress, Ca 2+ fluxes or mitochondrial dysfunction (29)(30)(31)(32). Recent studies have used this type of cells to look for transcriptional alterations to assess pathogenesis in ALS, and for example, an expression analysis of protein homeostasis pathways in the PBMCs of sALS patients had revealed alterations in the transcription of genes involved in the proteasome and autophagy processes [38].…”

Section: Discussionmentioning

confidence: 99%

“…There is increasing evidence that ALS has to be regarded as multisystem degeneration as it also presents non-motor symptoms [25,26]. In particular, peripheral blood mononuclear cells (PBMC) or skin fibroblasts display traits of the disease such as downregulation of Bcl-2 [27,28], increased nitrative stress [28], intracellular calcium dysregulation [29], glutamatergic dysfunction [30] and mitochondrial dysfunction [31] [32]. Regarding TDP-43 proteinopathy, it was reported mislocalization of TDP-43 in circulating lymphomonocytes from ALS patients carrying TARDBP mutations as well in some of sALS individuals [33], suggesting that cytoplasmic TDP-43 levels in peripheral cells could be a plausible biomarker for monitoring disease progression.…”

Section: Introductionmentioning

confidence: 99%

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Recapitulation of Pathological TDP-43 Features in Immortalized Lymphocytes from Sporadic ALS Patients

et al. 2018

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Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder of still unknown etiology that results in loss of motoneurons, paralysis, and death, usually between 2 and 4 years from onset. There are no currently available ALS biomarkers to support early diagnosis and to facilitate the assessment of the efficacy of new treatments. Since ALS is considered a multisystemic disease, here we have investigated the usefulness of immortalized lymphocytes from sporadic ALS patients to study TDP-43 homeostasis as well as to provide a convenient platform to evaluate TDP-43 phosphorylation as a novel therapeutic approach for ALS. We report here that lymphoblasts from ALS patients recapitulate the hallmarks of TDP-43 processing in affected motoneurons, such as increased phosphorylation, truncation, and mislocalization of TDP-43. Moreover, modulation of TDP-43 by an in-house designed protein casein kinase-1δ (CK-1δ) inhibitor, IGS3.27, reduced phosphorylation of TDP-43, and normalized the nucleo-cytosol translocation of TDP-43 in ALS lymphoblasts. Therefore, we conclude that lymphoblasts, easily accessible cells, from ALS patients could be a useful model to study pathological features of ALS disease and a suitable platform to test the effects of potential disease-modifying drugs even in a personalized manner.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Recapitulation of Pathological TDP-43 Features in Immortalized Lymphocytes from Sporadic ALS Patients

et al. 2018

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“…P2X7R expression was significantly reduced, leading to Ca 2+ disturbances in peripheral blood mononuclear cells in ALS patients ( Liu J. et al, 2016 ). Low concentrations of endogenous ATP acting on P2X7R induced motor neuron death ( Gandelman et al, 2013 ).…”

Section: Disorders Of the Central Nervous System (Cns)mentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

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Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

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“…Another study used exosomes to activate monocytes, and found that monocytes from ALS patients were less responsive than those from healthy individuals (109). ALS monocytes are less responsive to purinergic stimulation than those from controls (110).…”

Section: Monocyte Numbers and Proportionsmentioning

confidence: 99%

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is defined by loss of upper and lower motor neurons, associated with accumulation of protein aggregates in cells. There is also pathology in extra-motor areas of the brain, Possible causes of cell death include failure to deal with the aggregated proteins, glutamate toxicity and mitochondrial failure. ALS also involves abnormalities of metabolism and the immune system, including neuroinflammation in the brain and spinal cord. Strikingly, there are also abnormalities of the peripheral immune system, with alterations of T lymphocytes, monocytes, complement and cytokines in the peripheral blood of patients with ALS. The precise contribution of the peripheral immune system in ALS pathogenesis is an active area of research. Although some trials of immunomodulatory agents have been negative, there is strong preclinical evidence of benefit from immune modulation and further trials are currently underway. Here, we review the emerging evidence implicating peripheral immune alterations contributing to ALS, and their potential as future therapeutic targets for clinical intervention.

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Down-regulation of purinergic P2X7 receptor expression and intracellular calcium dysregulation in peripheral blood mononuclear cells of patients with amyotrophic lateral sclerosis

Cited by 30 publications

References 32 publications

Recapitulation of Pathological TDP-43 Features in Immortalized Lymphocytes from Sporadic ALS Patients

Recapitulation of Pathological TDP-43 Features in Immortalized Lymphocytes from Sporadic ALS Patients

Purinergic Signalling: Therapeutic Developments

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

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