Translational Medicine

Biography

Biography: Sushil Sharma

Abstract

Although extensive studies have been conducted to understand the cellular, molecular and genetic basis of progressive neurodegenerative diseases including Parkinson’s disease, Alzheimer’s disease, and drug addiction, there is lot to be learned before we can treat these devastating diseases more effectively. We discovered Charnoly Body (CB) as pre-apoptotic biomarker of compromised mitochondrial bioenergetics in developing undernourished rat Purkinje neurons and in hippocampal CA-3 and dentate gyrus neurons of intrauterine domoic acid exposed mice. CB formation is triggered by genetic and epigenetic changes, malnutrition, or in response to environmental neurotoxicity of PCBs and diesel exhaust nanoparticles. CBs are electron-dense, multi-lamellar (usually penta or hapta lamellar) membrane stacks that are formed due to condensation of degenerated mitochondrial membranes due to free radical overproduction and are involved in progressive neurodegeneration. Accumulation of CBs at the junction of axon hillock causes impaired axoplasmic transport of various enzymes, hormones, neurotransmitters, neurotropic factors, and mitochondria in the synaptic terminals to induce cognitive impairments in aging. During acute phase CBs are phagocytosed by lysosomes as a basic molecular mechanism of intracellular detoxification, however during chronic phase lysosomal-resistant CB sequestration induces cytochrome C, iron, caspase-3, and Bax release which causes apoptosis and further neurodegeneration. CB formation is associated with 18KDa TSPO delocalization and impaired intra-mitochondrial steriodogenesis involved in membrane stabilization and normal mitochondrial function. Homozygous weaver mutant (wv/wv) mice exhibit progressive neurodegeneration in the cerebellar and hippocampal regions due to CB formation. These genotypes exhibit early morbidity and mortality, which was attenuated by developing MTs over-expressing wv/wv mice. Mitochondrial bioenergetics was evaluated by using 14C-glucose in cultured neurons and by performing in-vivo microPET imaging with 18FdG. By developing mitochondrial genome knock out (RhOmgko) human dopaminergic (SK-N-SH) neurons as cellular model of aging and transfecting them with mitochondrial complex-1 gene (ubiquinone NADH-oxidoreductase), CB formation can be prevented by rejuvenating the mitochondrial genome with Metallothioneins (MTs). MTs prevented CB formation by serving as free radical scavengers. Hence any physiological or pharmacological intervention to augment MTs expression would inhibit CB formation and hence progressive neurodegenerative α-synucleinopathies and vice versa. Increase in α-synuclein index augments CB formation whereas MTs inhibit CB formation by inhibiting α-synuclein index. Initially Δψ collapse and 8-OH, 2dG may be determined as rudiments of CB formation to save time and money for cell tracking and drug development, subsequently CB may be detected at the ultra-structural level as a sensitive biomarker for early diagnosis and prognosis of progressive neurodegenerative diseases. Environmental protection, nutritional rehabilitation, antioxidants such as sirtuins, and moderate exercise could also prevent CB formation and hence early morbidity and mortality in progressive neurodegenerative diseases.