Apoptosis and Neurodegenerative Diseases
Development of Disease Specific Assays
Neurodegenerative diseases are becoming increasingly prevalent, especially in the Western societies, with larger percentage of members living to an older age. They have to be seen not only as a health problem, but since they are care-intensive, they also carry a significant economic burden.
Apoptotic pathways are induced in many of these diseases and are key culprits in disease progression.
Figure: Schematic representation of apoptotic pathways. Apoptosis triggered by internal (intrinsic) or external (extrinsic) stress signals that is activated by binding of ligands (e.g. FasL, APO-2L, TRAIL, TNF) to cell surface receptors (e.g. Fas, DR4, DR5, TNF-R1). The intrinsic apoptosis pathway might be triggered by p53 upon DNA damage following exposure to cellular stress. In the intrinsic pathway, death signal reaches mitochondria, leading to release of cytochrome c, which can binds to Apaf1. The cytochrome c/Apaf1 make a complex with pro-caspase-9 (in the presence of dATP), activates caspase-9, which promotes caspase-3 activation, eventually leading to cell death. The extrinsic pathway is initiated through the stimulation of the members of tumor necrosis factor receptor (TNF-R) family (transmembrane death receptors) by their respective ligands. These receptors activate pro-caspases-8, -10 by recruiting the endogenous adaptor protein FADD. Procaspase-8, -10 cleave themselves to form activated caspase-8 or -10. Ultimately, effector enzymes such as caspase-3, -6, -7 are activated in this cascade to mediate apoptosis. Likewise, there can be cross-talk between the intrinsic and extrinsic pathways. For example caspase-8 may cleave Bid to form tBid that is a strong activator of the intrinsic/mitochondrial apoptotic pathway. The intrinsic pathway is usually activated by the recruitment of BAX and BAK to outer mitochondrial membrane, causing cytochrome c release formation of apoptosome and subsequent activation of caspase-9. Activated caspase-9 proteolytically activates caspases-3, -6, and -7. Moreover, some of the effector caspases also can activate caspase-8, forming a positive amplification loop. doi:10.1016/j.pneurobio.2013.10.004.
Working with the Apoptosis Experts at Immunochemistry Technologies and Human Astroglial-Neuron Biosensors Experts at ArunA Biomedical, we plan on developing disease specific assays. Here's a map of the general process.