期刊
MOLECULAR NEUROBIOLOGY
卷 -, 期 -, 页码 -出版社
SPRINGER
DOI: 10.1007/s12035-021-02428-4
关键词
Neurodegeneration; Autoantibodies; Neurites; Cell death; RNAseq; Gene expression
资金
- Biomedical Laboratory Research and Development/Technology Transfer Program
- New Jersey Commission on Brain Injury Research [CBIRPIL007, TTP-001-20S]
- Congressionally Directed Gulf War Illness Research Program [W81XWH-16-1-0626]
- Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Rehabilitation/Biomedical Laboratory Research and Development) [RX001520, RX003253, BX005015]
- Veterans Bio-Medical Research Institute
This study found that circulating agonist autoantibodies targeting the 5-hydroxytryptamine 2A receptor, which increase in patients with Parkinson's disease, cognitive decline, and diabetes, can induce gene expression changes related to mitochondrial function, immune function, and cell death in neuroblastoma cells.
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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