Organelle Stress Sensors and Cell Death Mechanisms in Neurodegenerative Diseases
Abstract:Neurodegenerative diseases trigger neuronal cell death by a variety of endogenous suicide pathways. Although cell death may occur through highly heterogeneous processes, specific cell organelles and stress sensors have shown promise as potential therapeutic targets. The plasma membrane senses stress through residing receptors, which can directly or indirectly activate apoptosis. Importantly, several events involved in neuronal death also affect mitochondria homeostasis, leading to calcium uptake, opening of the permeability transition pore, and release of apoptogenic factors. In addition, nuclear DNA damage triggers cell death, where p53 is activated to modulate the expression of selected apoptosis target genes. Signaling proteins implicated in apoptosis pathways are enriched at the Golgi complex, including death receptors and the phosphoinositide 3-kinase. Finally, neurodegenerative diseases progress with accumulation of misfolded proteins, deficiently removed by intracellular proteases or chaperones, and transport abnormalities due to disturbance of cytoskeletal organization in degenerating neurons. The challenge is to decode the complex signaling network of inter-organellar crosstalk leading to cell death and identify therapeutic approaches for delaying or preventing neurodegenerative diseases.
Keywords: (SCA2); A-binding alcohol dehydrogenase; AMPA; Alzheimer's disease; Apoptosis; BDNF; CALNUC; CREB-binding protein; Down's syndrome; Drosophila huntingtin; Extrinsic apoptotic pathway activation; Fas-mediated apoptosi; GSK3; Huntington's disease; Minocycline; NMDA; PCD pathway; PERK-EIF2; Parkinson's disease; Programmed cell death; Rosiglitazone; SERCA; TNFR1; TUDCA; amyotrophic lateral sclerosis; anterograde transport; apoptosis inducing factor; autophagy; cell death; cell signaling; cerebellar degeneration; cyclosporin A; excitotoxicity; neurodegeneration; neuroprotection; organelles; permeability transition pore; phagolysosomes; phosphatidylserine; point-of-no-return; presenilin; rapamycin; retinitis pigmentosa; sphingomyelin; spinal muscular atrophy; stress sensors
Document Type: Research Article
Publication date: December 1, 2010
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