The LRRK2 signalling system

Price, Alice; Manzoni, Claudia; Cookson, Mark; Lewis, Patrick A.

doi:10.1007/s00441-017-2759-9

Cited by 38 publications

(39 citation statements)

References 84 publications

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“…LRRK2 encodes a 286-kDa protein with multiple functional domains; among the various mutations in LRRK2 , pathogenic mutations are primarily concentrated in the Ras of complex proteins (ROC) and the C-terminal of ROC (COR) domains, as well as in the kinase domain (G2019S and I2020T) ( Cookson, 2010 ). Since the discovery of the association between LRRK2 mutations and Parkinson’s disease, LRRK2 has been implicated in a variety of cellular functions, indicating that it is a multifunctional protein ( Drolet et al, 2011 ; Martin et al, 2014a ; Mata et al, 2006 ; Price et al, 2018 ; Wallings et al, 2015 ). In particular, LRRK2 has been implicated in the regulation of protein synthesis in Drosophila and in induced pluripotent stem cell (iPSC)-derived human neurons ( Imai et al, 2008 ; Martin et al, 2014b , 2014c ; Taymans et al, 2015 ); however, no specific disease-related translational target has yet been identified.…”

Section: Introductionmentioning

confidence: 99%

A Neuron-Glial Trans-Signaling Cascade Mediates LRRK2-Induced Neurodegeneration

2019

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SUMMARY Pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) induce an age-dependent loss of dopaminergic (DA) neurons. We have identified Furin 1, a pro-protein convertase, as a translational target of LRRK2 in DA neurons. Transgenic knockdown of Furin1 or its substrate the bone morphogenic protein (BMP) ligand glass bottom boat (Gbb) protects against LRRK2-induced loss of DA neurons. LRRK2 enhances the accumulation of phosphorylated Mad (pMad) in the nuclei of glial cells in the vicinity of DA neurons but not in DA neurons. Consistently, exposure to paraquat enhances Furin 1 levels in DA neurons and induces BMP signaling in glia. In support of a neuron-glial signaling model, knocking down BMP pathway members only in glia, but not in neurons, can protect against paraquat toxicity. We propose that a neuron-glial BMP-signaling cascade is critical for mediating age-dependent neurodegeneration in two models of Parkinson’s disease, thus opening avenues for future therapeutic interventions.

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Section: Introductionmentioning

confidence: 99%

A Neuron-Glial Trans-Signaling Cascade Mediates LRRK2-Induced Neurodegeneration

2019

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“…The molecular mechanisms linking LRRK2 to disease at a protein level have, as noted above, been the centre of much attention since 2004 (Alessi & Sammler, 2018). While a great deal of progress has been made, in particular with regard to the impact of coding variants on enzymatic function in the context of Parkinson's disease, there is still a level of divergence between the molecular consequences of different mutations (Price et al 2018). This may represent an underlying diversity in the pathways that link LRRK2 mutations to nigral degeneration; however, without a clearer understanding of the immediate signalling events surrounding LRRK2 it is also possible that the relevant molecular readouts for LRRK2 mutations have not yet been identified.…”

Section: Figure 4 Lrrk2 the Roco Kinases And Signal Transductionmentioning

confidence: 99%

Leucine rich repeat kinase 2: a paradigm for pleiotropy

Lewis

2019

The Journal of Physiology

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The LRRK2 gene, coding for leucine rich repeat kinase 2 (LRRK2), is a key player in the genetics of Parkinson's disease. Despite extensive efforts, LRRK2 has proved remarkably evasive with regard to attempts to understand both the role it plays in disease and its normal physiological function. At least part of why LRRK2 has been so difficult to define is that it appears to be many things to many cellular functions and diseases – a pleiotropic actor at both the genetic and the molecular level. Gaining greater insight into the mechanisms and pathways allowing LRRK2 to act in this manner will have implications for our understanding of the role of genes in the aetiology of complex disease, the molecular underpinnings of signal transduction pathways in the cell, and drug discovery in the genome era.

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“…The most frequent variation, affecting position 2019, results in an amino acid exchange from glycine to serine (G2019S) within a highly conserved DYG (aspartic acid/D, tyrosine/Y, glycine/G; or DFG [aspartic acid/D, phenylalanine/F, glycine/G] in most other kinases) motif in direct proximity to the activation loop of the kinase activity (Cookson, ; Kachergus et al., ; Mata, Wedemeyer, Farrer, Taylor, & Gallo, ). By today, several studies have reported that LRRK2 G2019S increases the kinase activity of the protein (first demonstrated by Jaleel et al., ; reviewed by Price and colleagues (Price, Manzoni, Cookson, & Lewis, )), while the effect of the I2020T variant (affecting the adjacent C‐terminal amino acid) on LRRK2 kinase activity has been discussed controversially (Gloeckner et al., ; Jaleel et al., ). Variants within or close to the ROC/COR domains (e.g.…”

Section: The Role Of Lrrk2 In the Pathogenesis Of Parkinson's Diseasementioning

confidence: 99%

Induced pluripotent stem cell‐based modeling of mutant LRRK2‐associated Parkinson's disease

Weykopf

Haupt

Jungverdorben

et al. 2019

Eur J of Neuroscience

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Recent advances in cell reprogramming have enabled assessment of disease‐related cellular traits in patient‐derived somatic cells, thus providing a versatile platform for disease modeling and drug development. Given the limited access to vital human brain cells, this technology is especially relevant for neurodegenerative disorders such as Parkinson's disease (PD) as a tool to decipher underlying pathomechanisms. Importantly, recent progress in genome‐editing technologies has provided an ability to analyze isogenic induced pluripotent stem cell (iPSC) pairs that differ only in a single genetic change, thus allowing a thorough assessment of the molecular and cellular phenotypes that result from monogenetic risk factors. In this review, we summarize the current state of iPSC‐based modeling of PD with a focus on leucine‐rich repeat kinase 2 (LRRK2), one of the most prominent monogenetic risk factors for PD linked to both familial and idiopathic forms. The LRRK2 protein is a primarily cytosolic multi‐domain protein contributing to regulation of several pathways including autophagy, mitochondrial function, vesicle transport, nuclear architecture and cell morphology. We summarize iPSC‐based studies that contributed to improving our understanding of the function of LRRK2 and its variants in the context of PD etiopathology. These data, along with results obtained in our own studies, underscore the multifaceted role of LRRK2 in regulating cellular homeostasis on several levels, including proteostasis, mitochondrial dynamics and regulation of the cytoskeleton. Finally, we expound advantages and limitations of reprogramming technologies for disease modeling and drug development and provide an outlook on future challenges and expectations offered by this exciting technology.

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The LRRK2 signalling system

Cited by 38 publications

References 84 publications

A Neuron-Glial Trans-Signaling Cascade Mediates LRRK2-Induced Neurodegeneration

A Neuron-Glial Trans-Signaling Cascade Mediates LRRK2-Induced Neurodegeneration

Leucine rich repeat kinase 2: a paradigm for pleiotropy

Induced pluripotent stem cell‐based modeling of mutant LRRK2‐associated Parkinson's disease

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