Charnoly body as a novel biomarker of nutritional stress in Alzheimer’s Disease
Journal Title: Functional Foods in Health and Disease - Year 2016, Vol 6, Issue 6
Abstract
Background: Charnoly body (CB) was discovered as universal biomarker of cell injury in the developing undernourished rat cerebellar Purkinje neurons and in the intrauterine Domoic acid and Kainic acid-exposed mice hippocampus and hypothalamic neurons. The incidence of CB increased with the severity of nutritional and environmental neurotoxic insult. Purpose: We proposed that stress (nutritional/environmental)-induced cortisol release augments, whereas metallothioneins (MTs), insulin-like growth factor (IGF-1), and brain-derived neurotropic factor (BDNF inhibit CB formation to prevent progressive neurodegeneration, early morbidity, and mortality in Alzheimer’s disease (AD). Results: CB is a pre-apoptotic biomarker of compromised mitochondrial bioenergetics and is formed in the most vulnerable cell in response to nutritional stress, intrauterine infection, environmental toxins, and/or drugs of abuse due to free radical overproduction and mitochondrial genome down-regulation. It appears as a pleomorphic, electron-dense multi-lamellar, quasi-crystalline stack of degenerated mitochondrial membranes in highly susceptible neurons and may be induced by microbial infection. CB formation was accompanied with stunted neuritogenesis in the aging mitochondrial genome knock out (RhOmgko) human dopaminergic (SK-N-SH, SHS-Y-5Y) neurons due to down-regulation of ubiquinone NADH oxidoreductase (complex-1). Transfection of RhOmgko neurons with ubiquinone NADH oxidoreductase (complex-1) gene and CoQ10, inhibited CB formation and augmented neuritogenesis, as confirmed in α-synuclein-metallothioneins triple knock out and weaver mutant mice. CB formation was attenuated in MTs-over-expressing weaver mutant mice. Findings: Accumulation of CB at the junction of axon hillock impairs axoplasmic transport of enzymes, neurotransmitters, hormones, neurotropic factors (NGF, BDNF), and mitochondria at the synaptic terminals to cause cognitive impairment, early morbidity, and mortality. Nonspecific induction of CB causes alopecia, myelosuppression, and GIT symptoms in multi-drug-resistant malignancies. Antioxidants and MTs inhibit CB formation as free radical scavengers by zinc-mediated transcriptional regulation of genes involved in growth, proliferation, differentiation, and development. Hence drugs may be developed to prevent CB formation and/or enhance charnolophagy as a basic molecular mechanism of intracellular detoxification to avert cognitive impairments in AD. Conclusion: Brain regional monoamine oxidase-specific CBs can be detected by 11C or 18F-labeled MAO-A or MAO-B inhibitors in vivo in addition to 18FdG-PET neuroimaging to quantitatively assess and improve the mitochondrial bioenergetics in AD.
Authors and Affiliations
Sushil Sharma, Joseph Choga, Vineet Gupta, Pearl Doghor, Ankur Chauhan, Fredy Kalala, Alison Foor, Christopher Wright, James Renteria, Krystel Elliot-Theberge, Shubhra Mathur
Keywords
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- EP ID EP457740
- DOI 10.31989/ffhd.v6i6.259
- Views 170
- Downloads 0
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