ArticleMolecular and cellular biology2015
A Pro-Nerve Growth Factor (proNGF) and NGF Binding Protein, α2-Macroglobulin, Differentially Regulates p75 and TrkA Receptors and Is Relevant to Neurodegeneration Ex Vivo and In Vivo.
Article in Molecular and cellular biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 51 citations in OpenAlex.
- Tear Biomarkers in Alzheimer's and Parkinson's Diseases, and Multiple Sclerosis: Implications for Diagnosis (Systematic Review).International journal of molecular sciences · 2022Pooled it
- Review
- ProNGF processing in adult rat tissues and bioactivity of NGF prodomain peptides.FEBS open bio · 2024Article
- Article
- A Pilot Study of Changes in the Level of Catecholamines and the Activity of α-2-Macroglobulin in the Tear Fluid of Patients with Parkinson's Disease and Parkinsonian Mice.International journal of molecular sciences · 2021Article
- Nerve growth factor (NGF) pathway biomarkers in Down syndrome prior to and after the onset of clinical Alzheimer's disease: A paired CSF and plasma study.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2021Article
- Recent progress in translational engineered in vitro models of the central nervous system.Brain : a journal of neurology · 2020Review
- Maternal Hyperhomocysteinemia Induces Neuroinflammation and Neuronal Death in the Rat Offspring Cortex.Neurotoxicity research · 2020Article
- GALNT6 promotes breast cancer metastasis by increasing mucin-type O-glycosylation of α2M.Aging · 2020Article
- A Membranome-Centered Approach Defines Novel Biomarkers for Cellular Subtypes in the Intervertebral Disc.Cartilage · 2020Article
- Cellular Trafficking of Amyloid Precursor Protein in Amyloidogenesis Physiological and Pathological Significance.Molecular neurobiology · 2019Review
- Neuroprotection: Pro-survival and Anti-neurotoxic Mechanisms as Therapeutic Strategies in Neurodegeneration.Frontiers in cellular neuroscience · 2019Review
- Alpha-2-Macroglobulin, a Hypochlorite-Regulated Chaperone and Immune System Modulator.Oxidative medicine and cellular longevity · 2019Review
- Deletion of p75Scientific reports · 2018Article
- Modulation of GSK-3 provides cellular and functional neuroprotection in the rd10 mouse model of retinitis pigmentosa.Molecular neurodegeneration · 2018Article
- N-Propargyl Caffeamide (PACA) Ameliorates Dopaminergic Neuronal Loss and Motor Dysfunctions in MPTP Mouse Model of Parkinson's Disease and in MPPMolecular neurobiology · 2018Article
- Inducible overexpression of endothelial proNGF as a mouse model to study microvascular dysfunction.Biochimica et biophysica acta. Molecular basis of disease · 2018Article
- Decreased serum proNGF concentration in patients with Parkinson's disease.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2018Article
- Article
- p75Cell death & disease · 2017Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Nerve growth factor (NGF) is generated from a precursor, proNGF, that is proteolytically processed. NGF preferentially binds a trophic tyrosine kinase receptor, TrkA, while proNGF binds a neurotrophin receptor (NTR), p75(NTR), that can have neurotoxic activity. Previously, we along with others showed that the soluble protein α2-macroglobulin (α2M) is neurotoxic. Toxicity is due in part to α2M binding to NGF and inhibiting trophic activity, presumably by preventing NGF binding to TrkA. However, the mechanisms remained unclear. Here, we show ex vivo and in vivo three mechanisms for α2M neurotoxicity. First, unexpectedly the α2M-NGF complexes do bind TrkA receptors but do not induce TrkA dimerization or activation, resulting in deficient trophic support. Second, α2M makes stable complexes with proNGF, conveying resistance to proteolysis that results in more proNGF and less NGF. Third, α2M-proNGF complexes bind p75(NTR) and are more potent agonists than free proNGF, inducing tumor necrosis factor alpha (TNF-α) production. Hence, α2M regulates proNGF/p75(NTR) positively and mature NGF/TrkA negatively, causing neuronal death ex vivo. These three mechanisms are operative in vivo, and α2M causes neurodegeneration in a p75(NTR)- and proNGF-dependent manner. α2M could be exploited as a therapeutic target, or as a modifier of neurotrophin signals.
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