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Pathogenic Mechanisms


In considering pathogenic mechanisms associated with Parkinson’s disease, the compound advisory committee for CINAPS identified reagents that could potentially target: 1) enhanced alpha-synuclein degradation or increased misfolded protein clearance through enhancement of chaperone expression or stabilization--candidate compounds include rapamycin (sirolimus), celastrol, geldanamycin; 2) reagents that could lead to reduced oxidative stress--candidate compounds include CDP choline, celastrol, melatonin, R-lipoic acid   3) reagents that could reduce excitotoxic cell death--candidate compounds include memantine, isradipine;   4) reagents that reduce neuroinflammation--candidate compounds include melatonin, celastrol, perindopril, pioglitazone; 5) reagents that diminish mitochondrial dysfunction--compounds include mitoQ, an enantiomer of pramipexole, R-lipoic acid, isradipine, dimebon; and 6) reagents that specifically address pathways associated with genetic forms of Parkinson’s disease. Details for each mechanistic pathway identified are provided below:

 

Synuclein  

Events in α-synuclein toxicity. The central panel shows the major pathway for protein aggregation. Monomeric α-synuclein is natively unfolded in solution but can also bind to membranes in an α-helical form. It seems likely that these two species exist in equilibrium within the cell, although this is unproven. From in vitro work, it is clear that unfolded monomer can aggregate first into small oligomeric species that can be stabilized by β-sheet-like interactions and then into higher molecular weight insoluble fibrils. In a cellular context, there is some evidence that the presence of lipids can promote oligomer formation: α-synuclein can also form annular, pore-like structures that interact with membranes. The deposition of α-synuclein into pathological structures such as Lewy bodies is probably a late event that occurs in some neurons. On the left hand side are some of the known modifiers of this process. Electrical activity in neurons changes the association of α-synuclein with vesicles and may also stimulate polo-like kinase 2 (PLK2), which has been shown to phosphorylate α-synuclein at Ser129. Other kinases have also been proposed to be involved. As well as phosphorylation, truncation through proteases such as calpains, and nitration, probably through nitric oxide (NO) or other reactive nitrogen species that are present during inflammation, all modify synuclein such that it has a higher tendency to aggregate. The addition of ubiquitin (shown as a black spot) to Lewy bodies is probably a secondary process to deposition. On the right are some of the proposed cellular targets for α-synuclein mediated toxicity, which include (from top to bottom) ER-golgi transport, synaptic vesicles, mitochondria and lysosomes and other proteolytic machinery. In each of these cases, it is proposed that α-synuclein has detrimental effects, listed below each arrow, although at this time it is not clear if any of these are either necessary or sufficient for toxicity in neurons. Mark R. Cookson,  Molecular Neurodegeneration 2009 4:9 doi:10.1186/1750-1326-4-9.

Mitochondrial dysfunction  

Hypothetic scheme of aging-induced vascular dysfunction and the role of mitochondria in this process. Aging-induced mitochondrial dysfunction triggers mitochondrial reactive oxygen species (mtROS) formation from respiratory complexes I, II, and III (Q = ubiquinone). Break-down of mtROS is catalyzed by glutathione peroxidase (GPx, for H2O2) or manganese superoxide dismutase (MnSOD), the latter is in turn inhibited by mitochondrial peroxynitrite (ONOO−) formation. mtROS increase the levels of toxic aldehydes and inhibit the mitochondrial aldehyde dehydrogenase (ALDH-2), the detoxifying enzyme of those aldehydes. Increase in mtROS and toxic aldehydes also leads to mtDNA strand breaks which leads to augmented dysfunction in respiratory chain complexes and further increase in mtROS since mtDNA encodes mainly for those respiratory complexes. mtROS also activates mitochondrial permeability transition pore (mPTP), which upon opening releases mtROS to the cytosol leading to protein kinase C (PKC)-dependent NADPH oxidase activation, eNOS uncoupling and finally to endothelial dysfunction. Cytosolic reactive oxygen and nitrogen species (ROS/RNS) in turn were demonstrated to activate KATP channels, which causes alterations in mitochondrial membrane potential (Ψ) and further augments mtROS levels.

Genetic contributions

Last updated December 23, 2013