Models for LRRK2-Linked Parkinsonism

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by the selective loss of dopaminergic neurons and the presence of Lewy bodies. The pathogenesis of PD is not fully understood, but it appears to involve both genetic susceptibility and environmental factors. Treatment for PD that prevents neuronal death progression in the dopaminergic system and abnormal protein deposition in the brain is not yet available. Recently, mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified to cause autosomal-dominant late-onset PD and contribute to sporadic PD. Here, we review the recent models for LRRK2-linked Parkinsonism and their utility in studying LRRK2 neurobiology, pathogenesis, and potential therapeutics.

Non-Motor and Motor Features in LRRK2 Transgenic Mice

“…Several animal models for PD have been developed, but most of them focus on motor and neuropathological features and they do not recapitulate entirely clinical PD [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]. Recently, Li and collaborators have created a mouse line that sums up the main features of human PD [22].…”

LDN-73794 Attenuated LRRK2-Induced Degeneration in a <i>Drosophila</i> Parkinson’s Disease Model

“…These results suggest that inhibition of LRRK2 kinase activity can be a potential therapeutic strategy for PD intervention and LDN-73794 could be a potential lead compound for developing novel therapeutics. LRRK2 kinase activity is altered by several disease-linked LRRK2 mutations in the GTPase or kinase domain including R1441C, R1441H, R1441G, Y1699C, G2019S, and I2020T [12] [18] [36]. The most common PDlinked mutation, G2019S, contributes to about 40% of genetic PD cases and some of the sporadic PD cases as well [37].…”

“…One of the barriers to developing protective compounds is that rodent in vivo genetic testing models require a very long experimental time period. Moreover, LRRK2 transgenic rodent models [36] lack DA neuron degeneration or only display subtle degeneration, which hinders the drug testing [36].…”

“…Unlike LRRK2 transgenic mouse models [36], flies expressing mutant LRRK2 displays severe motor dysfunction and selective DA neuron degeneration [34]. The Drosophila model provides a critical testing tool linked between in vitro model testing and clinical trials for developing PD-related compounds.…”

68 and FX2149 Attenuate Mutant LRRK2-R1441C-Induced Neural Transport Impairment

“…LRRK2-associated PD cases have pleomorphic pathology, however the physiological function of LRRK2 is largely undetermined. LRRK2 is a large 286 kDa cytoplasmic protein and contains several functional domains (Li et al, 2011). Studies suggest that LRRK2 is involved in multiple cellular processes, including cytoskeletal organization, neuronal outgrowth, mitochondrial dynamics, autophagy, endocytosis, and protein interactions (Mata et al, 2006; Raquel Esteves et al, 2014).…”