Circulating Neurotoxic 5-HT2A Receptor Agonist Autoantibodies in Adult Type 2 Diabetes with Parkinson’s Disease

Zimering, Mark B

doi:10.15226/2374-6890/5/2/00102

Cited by 9 publications

(29 citation statements)

References 32 publications

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“…Rho signaling is involved in several cerebral diseases, including intellectual disability (ID), epilepsy, drug addiction, HD, amyotrophic lateral sclerosis (ALS), and AD, and it acts by regulating axonogenesis, neuronal migration and synaptic plasticity (Table 3) (Mendoza-Naranjo et al, 2007; Locke et al, 2009; Zhang Y. et al, 2015; Li et al, 2016; Wang et al, 2017; Zimering, 2018; Costain et al, 2019). Rac1 and Rac3 are associated with intelligence by regulating key cellular functions in the central nervous system (Reijnders et al, 2017; Costain et al, 2019).…”

Section: The Rho Subfamily In Non-neoplastic Cerebral Diseasesmentioning

confidence: 99%

The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases

Qu¹,

Pan²,

et al. 2019

Front. Mol. Neurosci.

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The small GTPases from the Ras superfamily play crucial roles in basic cellular processes during practically the entire process of neurodevelopment, including neurogenesis, differentiation, gene expression, membrane and protein traffic, vesicular trafficking, and synaptic plasticity. Small GTPases are key signal transducing enzymes that link extracellular cues to the neuronal responses required for the construction of neuronal networks, as well as for synaptic function and plasticity. Different subfamilies of small GTPases have been linked to a number of non-neoplastic cerebral diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), intellectual disability, epilepsy, drug addiction, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and a large number of idiopathic cerebral diseases. Here, we attempted to make a clearer illustration of the relationship between Ras superfamily GTPases and non-neoplastic cerebral diseases, as well as their roles in the neural system. In future studies, potential treatments for non-neoplastic cerebral diseases which are based on small GTPase related signaling pathways should be explored further. In this paper, we review all the available literature in support of this possibility.

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Section: The Rho Subfamily In Non-neoplastic Cerebral Diseasesmentioning

confidence: 99%

The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases

Qu¹,

Pan²,

et al. 2019

Front. Mol. Neurosci.

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“…A possible role for brain reactive autoantibodies was suggested by prior studies [6] including our report that plasma IgG autoantibodies in a subset of chronic schizophrenia potently suppressed neurite outgrowth and mediated strong depolarization in N2A mouse neuroblastoma cells [8]. Since major depression and Parkinson's disease autoantibodies mediated long-lasting 5-HT2A receptor activation positively coupled to Gq/11 signaling [9,10], here we tested whether chronic paranoid schizophrenia plasma autoantibodies activate 5-HT2A receptor, Gq/11-mediated signaling leading to neurite outgrowth inhibition in N2A mouse neuroblastoma cells. A role for signaling cross-talk involving 5-HT2AR/mGlu2R heteromers was tested by comparing N2A acute neurite retraction induced by schizophrenia plasma autoantibodies in the presence or absence of the mGlu2/3R agonist LY379268.…”

Section: Introductionmentioning

confidence: 83%

“…Acute neurite retraction assay: % of basal neurite length in N2A cells expressing one or more proximally-located dendrite-like process was determined after interval exposure to test substances as previously reported [10].…”

Section: Patientmentioning

confidence: 99%

“…N2A cell survival: MTT assay was performed 24 hours after incubation with test substances as previously reported [10].…”

Section: Patientmentioning

confidence: 99%

“…Major depressive disorder and Parkinson's disease plasma IgG autoantibodies were previously reported to cause acute N2A neurite retraction through a mechanism involving activation of the RhoA/ Rho kinase and PLC/IP3R/Ca2+ signaling pathways [9,10]. In the present study, neurite retraction induced by SCZ plasma IgG autoantibodies was completely prevented by co-incubating N2A cells with a ten micromolar concentration of the selective Rho kinase inhibitor Y27632 or a one micromolar concentration of the selective Gq11 inhibitor Y254890 (Table 3).…”

Section: Mechanism Of Schizophrenia Plasma Igg-induced Neurite Retracmentioning

confidence: 99%

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Schizophrenia Plasma Autoantibodies Promote ‘Biased Agonism’ at the 5-Hydroxytryptamine 2A Receptor: Neurotoxicity is Positively Modulated by Metabotropic Glutamate 2/3 Receptor Agonism

Zimering

Nadkarni

2019

Endocrinol Diabetes Metab J

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Aims: To test whether neurite-inhibitory plasma autoantibodies in chronic schizophrenia activate Gq/11-and Gi-coupled signaling pathways downstream of 5-hydroxytryptamine 2A receptor activation; and for modulation of serotonergic signaling by the metabotropic 2/3 receptor agonist LY379268. Methods: Plasma from five older adults with chronic schizophrenia and eight age-matched patients having another neuropsychiatric, immune or metabolic disorder was subjected to Protein-A affinity chromatography to obtain IgG autoantibodies. Mean neurite retraction (5 minutes) or cell survival (24 hours) was determined in mouse N2A neuroblastoma cells incubated with autoantibodies in the presence or absence of specific antagonists of the Gq/11/PLC/IP3R signaling pathway, Gi-coupled, beta-arrestin2-directed pathways, or LY379268. Results: Chronic schizophrenia plasma autoantibodies-mediated dose-and time-dependent acute N2A neurite retraction was completely prevented by M100907, a selective 5-hydroxytryptamine 2A receptor antagonist. LY379268 promoted autoantibody-induced neurite retraction causing a shift-to-theleft in the dose-response curve. Antagonists of the RhoA/Rho kinase and Gq/11/PLC/IP3R signaling pathways blocked autoantibody-mediated neurite retraction. Chronic schizophrenia plasma autoantibodies mediated increased N2A cell survival which was blocked by LY379268, pertussis toxin, and antagonists of PI3-kinase-mediated survival signaling. Conclusion: Schizophrenia plasma autoantibodies activate the 5-hydroxytryptamine 2A receptor positively coupled to Gq/11/PLC/IP3R pathway and RhoA/Rho kinase signaling activation in promoting acute N2A cell neurite retraction. Autoantibodies in a subset of patients experiencing hallucinations promoted increased N2A cell survival mediated (in part) via a pertussis-toxin sensitive, Gi-coupled, PI3-kinase-dependent mechanism. Positive modulation of 5-HT2AR-mediated neurite retraction by LY379268 suggests the autoantibodies may target (in part) the 5-HT2AR/mGlu2R heteromer.

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Gene Expression Changes in a Model Neuron Cell Line Exposed to Autoantibodies from Patients with Traumatic Brain Injury and/or Type 2 Diabetes

2021

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Traumatic brain injury and adult type 2 diabetes mellitus are each associated with the late occurrence of accelerated cognitive decline and Parkinson’s disease through unknown mechanisms. Previously, we reported increased circulating agonist autoantibodies targeting the 5-hydroxytryptamine 2A receptor in plasma from subsets of Parkinson’s disease, dementia, and diabetic patients suffering with microvascular complications. Here, we use a model neuron, mouse neuroblastoma (N2A) cell line, to test messenger RNA expression changes following brief exposure to traumatic brain injury and/or type 2 diabetes mellitus plasma harboring agonist 5-hydroxytryptamine 2A receptor autoantibodies. We now report involvement of the mitochondrial dysfunction pathway and Parkinson’s disease pathways in autoantibody-induced gene expression changes occurring in neuroblastoma cells. Functional gene categories upregulated significantly included cell death, cytoskeleton-microtubule function, actin polymerization or depolymerization, regulation of cell oxidative stress, mitochondrial function, immune function, protein metabolism, and vesicle function. Gene categories significantly downregulated included microtubule function, cell adhesion, neurotransmitter release, dopamine metabolism synaptic plasticity, maintenance of neuronal differentiation, mitochondrial function, and cell signaling. Taken together, these results suggest that agonist 5-hydroxytryptamine receptor autoantibodies (which increase in Parkinson’s disease and other forms of neurodegeneration) mediate a coordinating program of gene expression changes in a model neuron which predispose to neuro-apoptosis and are linked to human neurodegenerative diseases pathways.

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Circulating Neurotoxic 5-HT2A Receptor Agonist Autoantibodies in Adult Type 2 Diabetes with Parkinson’s Disease

Cited by 9 publications

References 32 publications

The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases

The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases

Schizophrenia Plasma Autoantibodies Promote ‘Biased Agonism’ at the 5-Hydroxytryptamine 2A Receptor: Neurotoxicity is Positively Modulated by Metabotropic Glutamate 2/3 Receptor Agonism

Gene Expression Changes in a Model Neuron Cell Line Exposed to Autoantibodies from Patients with Traumatic Brain Injury and/or Type 2 Diabetes

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