Delaying aging is neuroprotective in Parkinson’s disease: a genetic analysis in C. elegans models

Abstract

Aging is the greatest risk factor for the development of Parkinson’s disease (PD). However, the role of aging in the pathogenesis of PD is not known and it is currently uncertain why the symptoms take many decades to develop when inherited mutations that cause the disease can be present from birth. We hypothesize that there are specific changes that take place during the aging process that make cells susceptible to disease-causing mutations that are well-tolerated at younger ages. If so, then interventions that increase lifespan should be beneficial in the treatment of PD. To test this hypothesis, we used the powerful genetics of C. elegans, as this worm has been used extensively in aging research. We crossed transgenic worm models of PD expressing either human mutant α-synuclein (A53T) or LRRK2 (G2019S) with the long-lived insulin-IGF1 receptor mutant, daf-2. The daf-2 mutation increased the lifespan of both PD mutants. The increase in lifespan resulting from the daf-2 mutation rescued the degeneration of dopamine neurons in both worm models of PD and importantly rescued deficits in dopamine-dependent behaviors including basal slowing, ethanol avoidance, and area-restricted searching. Increasing lifespan through daf-2 mutation also delayed the formation of small aggregates in a worm model of PD expressing α-synuclein in the body wall muscle and rescued deficits in resistance to different stresses that were present in the PD mutant worms. Overall, this work suggests that slowing down the aging process may provide an effective treatment for PD.

Aging and Parkinson's disease: Different sides of the same coin?

“…Even dominantly inherited genetic forms of PD require the passage of time, often decades, for PD symptoms to emerge. Without aging, degenerative changes in DA neurons are not fully expressed in PD genetic models in C. elegans and human iPSCs, and the expression of genes strongly associated with PD are uniformly regulated by aging in a disease‐promoting direction . On the flip side, aging is not PD.…”

“…The worm C. elegans provides a powerful experimental approach for studying the genetics of aging and PD. A recent report by Cooper and colleagues examined the effects of delaying aging on the phenotype of worms harboring human PD mutations in α‐syn or leucine‐rich repeat kinase 2 (LRRK2), specifically in DA neurons. PD‐mutant worms exhibited normal development and lifespan, but expressed a phenotype that included deficits in dopamine‐dependent behaviors, greater sensitivity to stressors, and accelerated DA neuron degeneration.…”

Genetically engineered animal models of Parkinson's disease: From worm to rodent

“…C. elegans overexpressing human WT or mutant α-syn using pan-neuronal-(aex-3) or dopamine-directed (dat) promoter present significant decrease in the number of dopaminergic neurons (Table 5) in the cephalic neurons, anterior deirid and posterior deirid (Cao, Yuan, Pehek, Moise & Huang, 2010;Cooper, Dues, Spielbauer, Machiela & Senchuk, 2015;Lakso et al, 2003). Interestingly, overexpression of human WT or mutant LRKK2 protein (G2019S, R1441C) in C. elegans is associated with a drop in the levels of DA and DA transporters, which is more pronounced in transgenic organisms bearing the mutated forms of the gene (Table 7) (Saha, Guillily, Ferree, Lanceta & Chan, 2009;Yao et al, 2010).…”

Measuring Oxidative Stress in Caenorhabditis elegans: Paraquat and Juglone Sensitivity Assays

“…References in which this protocol was used: Van Raamsdonk and Hekimi, 2009; 2012; Van Raamsdonk et al, 2010; Cooper et al, 2015; Schaar et al, 2015; Dues et al, 2016; Machiela et al, 2016.…”