C. elegans Model Identifies Genetic Modifiers of α-Synuclein Inclusion Formation During Aging

Abstract

Inclusions in the brain containing α-synuclein are the pathological hallmark of Parkinson's disease, but how these inclusions are formed and how this links to disease is poorly understood. We have developed a C. elegans model that makes it possible to monitor, in living animals, the formation of α-synuclein inclusions. In worms of old age, inclusions contain aggregated α- synuclein, resembling a critical pathological feature. We used genome-wide RNA interference to identify processes involved in inclusion formation, and identified 80 genes that, when knocked down, resulted in a premature increase in the number of inclusions. Quality control and vesicle-trafficking genes expressed in the ER/Golgi complex and vesicular compartments were overrepresented, indicating a specific role for these processes in α-synuclein inclusion formation. Suppressors include aging-associated genes, such as sir-2.1/SIRT1 and lagr-1/LASS2. Altogether, our data suggest a link between α-synuclein inclusion formation and cellular aging, likely through an endomembrane-related mechanism. The processes and genes identified here present a framework for further study of the disease mechanism and provide candidate susceptibility genes and drug targets for Parkinson's disease and other α-synuclein related disorders.

Scalable electrophysiology in intact small animals with nanoscale suspended electrode arrays

“…While common phenotyping metrics such as paralysis and lifespan make PD and ALS worm models almost indistinguishable 44,45 , we found that using multiple electrophysiological metrics based on nano-SPEAR recordings allows us to clearly differentiate between the two disease models (Fig. 5b).…”

“…The disease models used were NL5901 (PD) and the ALS strain was obtained from Jiou Wang from the work conducted in Wang, 2009 et al 4 . Specifically these disease models express alpha-synuclein (α-syn) fused to YFP in the body-wall muscles (PD worms) 5 and the G85R mutation of SOD1 fused to YFP in all neurons (ALS worms) 4 . All strains were maintained at approximately 21°C on nematode growth medium (NGM) seeded with OP50, unless stated otherwise.…”

“…To demonstrate how nano-SPEARs can facilitate the study of neurological diseases, we selected C. elegans models for PD and ALS 44,45 . These diseases are modeled by heterologous expression of human genes implicated in disease pathogenesis, namely, alpha-synuclein (α-syn) for PD and G85R Cu, Zn-superoxide dismutase-1 (SOD1) for ALS.…”

“…These diseases are modeled by heterologous expression of human genes implicated in disease pathogenesis, namely, alpha-synuclein (α-syn) for PD and G85R Cu, Zn-superoxide dismutase-1 (SOD1) for ALS. While reduced animal locomotion and cell loss have been shown in these disease models 44,45 , the electrophysiological phenotypes remain unknown, likely due to the difficulty of performing electrophysiology.…”

“…While more work is needed to understand why ALS and PD models show such different electrophysiological phenotypes, one explanation is the fact that each disease model expresses the respective disease-related gene in a different group of cells: ALS is modeled in neurons while PD is modeled in the body-wall muscle itself 44,45 . This hypothesis suggests that synaptic input in ALS worms may reduce overall excitatory input to the body-wall muscle without affecting their relative health and mean ISI.…”