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- Title
Charnoly body as a novel biomarker of nutritional stress in Alzheimer's Disease.
- Authors
Sharma, Sushil; Choga, Joseph; Gupta, Vineet; Doghor, Pearl; Chauhan, Ankur; Kalala, Fredy; Foor, Alison; Wright, Christopher; Renteria, James; Elliott-Theberge, Krystel; Mathur, Shubhra
- Abstract
Background: The Charnoly body (CB) was discovered as a 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 and 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, formed in the most vulnerable cell in response to nutritional stress, intrauterine infection, environmental toxins, and/or drug abuse due to free radical overproduction and mitochondrial genome downregulation. 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 a-synucleinmetallothioneins triple knock out and weaver mutant mice. CB formation was attenuated in MTsover- 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 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 zincmediated transcriptional regulation of genes involved in growth, proliferation, differentiation, and development. Consequently, 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 18Flabeled MAO-A or MAO-B inhibitors in vivo, in addition to 18FdG-PET neuroimaging to quantitatively assess and improve the mitochondrial bioenergetics in AD.
- Subjects
BIOMARKERS; ALZHEIMER'S disease; DOMOIC acid; KAINIC acid; NEUROPHARMACOLOGY; SOMATOMEDIN C; BRAIN-derived neurotrophic factor; MITOCHONDRIAL DNA
- Publication
Functional Foods in Health & Disease, 2016, Vol 6, Issue 6, p344
- ISSN
2378-7007
- Publication type
Article
- DOI
10.31989/ffhd.v6i6.259