Anavex Life Sciences Corp (AVXL)

[georgejjl]

Protein Misfolding and Accumulation as Root Cause in Neurodegeneration

Impairment of catabolic pathways in AD and PD. AD- In AD cells, ?tau and A42 , produced by caspase3 (1) and BACE1/?-complex (2) cleavage respectively, are aggregated in oligomers and PHFs. Aggregates of A42 and ubquitinated ?tau, which cannot be degraded by UPS (3), enter in macroautophagic catabolic pathway (4). AVs fuse with endosomes recycled from plasma membrane resulting in amphisomes, suitable milieu for further A42 production (5). The number of AVs and amphisomes, unable to fuse with lysosomes, increases, and the incomplete macroautophagy process leads to exophagy of vescicles containing A42 and ubquitinated ?tau aggregates (6). A42, in turn, sustains autophagy activation (7), inhibits proteasome (8), and induces ROS production and damageto mitochondria, favoring aggregate formation. PD- Soluble (1) and oligomeric (2) a-synuclein is degraded by both UPS and autophagy. Aggegated (3) a-synuclein cannot be degraded by UPS. Mutant and oxidant-modified forms of a-synuclein (4) bind abnormally to Lamp2A leading to blockage of their own degradation as well as degradation of other CMA substrates. An induction of macroautophagy occurs, characterized by an increased number of AVs (5) which are unable to fuse with lysosomes thus leading to an incomplete macroautophagy process. As a result, damaged mitochondria (6) accumulate, with consequent ROS production (7) responsible for a further UPS inhibition and oxidation of a-synuclein (4) in a vicious loop.

http://austinpublishinggroup.com/aapd/fulltext/aapd-v1-id1016.php

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