Modelling the functional genomics of Parkinson’s disease inCaenorhabditis elegans:LRRK2and beyond

Abstract

For decades, Parkinson’s disease (PD) cases have been genetically categorised into familial, when caused by mutations in single genes with a clear inheritance pattern in affected families, or idiopathic, in the absence of an evident monogenic determinant. Recently, genome-wide association studies (GWAS) have revealed how common genetic variability can explain up to 36% of PD heritability and that PD manifestation is often determined by multiple variants at different genetic loci. Thus, one of the current challenges in PD research stands in modelling the complex genetic architecture of this condition and translating this into functional studies. Caenorhabditis elegans provide a profound advantage as a reductionist, economical model for PD research, with a short lifecycle, straightforward genome engineering and high conservation of PD relevant neural, cellular and molecular pathways. Functional models of PD genes utilising C. elegans, show many phenotypes recapitulating pathologies observed in PD. When contrasted with mammalian in vivo and in vitro models, these are frequently validated, suggesting relevance of C. elegans in the development of novel PD functional models. This review will discuss how the nematode C. elegans PD models have contributed to the uncovering of molecular and cellular mechanisms of disease, with a focus on the genes most commonly found as causative in familial PD and risk factors in idiopathic PD. Specifically, we will examine the current knowledge on a central player in both familial and idiopathic PD, Leucine-rich repeat kinase 2 (LRRK2) and how it connects to multiple PD associated GWAS candidates and Mendelian disease-causing genes.

An updatedC. elegansnuclear body muscle transcriptome for studies in muscle formation and function

“…The physiology of its body muscle shares a high degree of similarity to the skeletal muscle of vertebrates with several mutually conserved genes (Lecroisey et al 2007; Gieseler et al 2017; Hrach et al 2020; Ellwood et al 2021b). In addition, C. elegans is a popular choice for studying disorders affecting humans, including muscular dystrophy (Hrach et al 2020; Chaya et al 2021; Ellwood et al 2021a), since many human disease genes when introduced to worms phenocopy the symptoms (Markaki and Tavernarakis 2020; Natale et al 2020; Chandler et al 2021; Yue et al 2021).…”

“…In addition, over 200 proteins have been identified in C. elegans to be essential for the assembly, maintenance, and function of the sarcomere, many of which have human orthologs [2]. C. elegans is also a popular choice for studying disorders affecting humans, including muscular dystrophy [3][4][5], since many human disease genes, when introduced in worms phenocopy the symptoms [6][7][8][9].…”

LRRK2 Structure-Based Activation Mechanism and Pathogenesis

“…Through genome-wide association studies, about 20 PD-associated genes have been identified so far, including alpha-synuclein ( SNCA ), glucocerebrosidase ( GBA ), and Leucine-rich-repeat kinase 2 ( LRRK2 ) [ 2 , 3 ]. LRRK2 is a commonly mutated gene that emerges in both sporadic and familial PD [ 4 ]. Furthermore, recently, it was found that LRRK2 kinase activity was enhanced in idiopathic PD postmortem brain tissue [ 5 ].…”

Aligning Cross-Species Interactomes for Studying Complex and Chronic Diseases

“…elegans is a widely used model organism in biological research due to its wellcharacterized and straightforward anatomy. Although C. elegans does not develop any neurodegenerative diseases because it lacks certain key features of the human brain, it has been used to study various neurodegenerative disorders, including AD and PD [21][22][23].…”