The development of inhibitors of leucine‐rich repeat kinase 2 (LRRK2) as a therapeutic strategy for Parkinson's disease: the current state of play

Azeggagh, Sonia; Berwick, Daniel C.

doi:10.1111/bph.15575

Cited by 44 publications

(33 citation statements)

References 152 publications

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“…There is currently no cure for PD, and dopamine replacement using l -dehydroxyphenylalanine ( l -DOPA) remains the primary treatment. l -DOPA is quite useful in lowering motor symptoms; nonetheless, there are two key issues: adverse effects and patients becoming medication-resistant [ 2 ]. Moreover, it is critical to emphasize that current PD therapies only reduce symptoms and do not slow or stop disease progression.…”

Section: Introductionmentioning

confidence: 99%

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Thakur

Kumar

Lee

et al. 2022

Genes

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Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease, characterized by the specific loss of dopaminergic neurons in the midbrain. The pathophysiology of PD is likely caused by a variety of environmental and hereditary factors. Many single-gene mutations have been linked to this disease, but a significant number of studies indicate that mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are a potential therapeutic target for both sporadic and familial forms of PD. Consequently, the identification of potential LRRK2 inhibitors has been the focus of drug discovery. Various investigations have been conducted in academic and industrial organizations to investigate the mechanism of LRRK2 in PD and further develop its inhibitors. This review summarizes the role of LRRK2 in PD and its structural details, especially the kinase domain. Furthermore, we reviewed in vitro and in vivo findings of selected inhibitors reported to date against wild-type and mutant versions of the LRRK2 kinase domain as well as the current trends researchers are employing in the development of LRRK2 inhibitors.

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Section: Introductionmentioning

confidence: 99%

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Thakur

Kumar

Lee

et al. 2022

Genes

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“…Autosomal dominant PD mutations that activate LRRK2 kinase interfere with the formation of primary cilia through a pathway involving pRab8a/10 binding to RILPL1 (Dhekne et al , 2018). LRRK2 kinase inhibitors are currently in phase 1 and 2 clinical trials with PD patients (Azeggagh & Berwick, 2021), while alternative strategies to antagonize LRRK2 signalling could be beneficial for future therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Structural basis for the specificity of PPM1H phosphatase for Rab GTPases

et al. 2021

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LRRK2 serine/threonine kinase is associated with inherited Parkinson’s disease. LRRK2 phosphorylates a subset of Rab GTPases within their switch 2 motif to control their interactions with effectors. Recent work has shown that the metal‐dependent protein phosphatase PPM1H counteracts LRRK2 by dephosphorylating Rabs. PPM1H is highly selective for LRRK2 phosphorylated Rabs, and closely related PPM1J exhibits no activity towards substrates such as Rab8a phosphorylated at Thr72 (pThr72). Here, we have identified the molecular determinant of PPM1H specificity for Rabs. The crystal structure of PPM1H reveals a structurally conserved phosphatase fold that strikingly has evolved a 110‐residue flap domain adjacent to the active site. The flap domain distantly resembles tudor domains that interact with histones in the context of epigenetics. Cellular assays, crosslinking and 3‐D modelling suggest that the flap domain encodes the docking motif for phosphorylated Rabs. Consistent with this hypothesis, a PPM1J chimaera with the PPM1H flap domain dephosphorylates pThr72 of Rab8a both in vitro and in cellular assays. Therefore, PPM1H has acquired a Rab‐specific interaction domain within a conserved phosphatase fold.

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“…Murine models with loss of function mutations in Rab38 precisely phenocopy the effects of LRRK2 kinase inhibition/knockout in alveolar Type II pneumocytes. 28, 48 Given that LRRK2 kinase inhibitors are in clinical trials, 49 that LRRK2 inhibitor-induced lung defects are striking, 28 and that animal studies interpreted to show reversibility of inhibitor-induced lung defects utilized short (2 week) inhibitor treatment, 29 it is vitally important to define LRRK2’s role in normal alveolar function. More broadly, our work suggests that non-neuronal cell types expressing high levels of LRRK2 are tractable systems which can help define potentially disease-relevant LRRK2 cellular functions.…”

Section: Discussionmentioning

confidence: 99%

Endogenous Rab38 regulates LRRK2’s membrane recruitment and substrate Rab phosphorylation in melanocytes

Unapanta

Shavarebi

Porath

et al. 2022

Preprint

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Point mutations in LRRK2 cause Parkinson's Disease and augment LRRK2's kinase activity. However, cellular pathways that enhance LRRK2 kinase function have not been identified. While overexpressed Rab29 draws LRRK2 to Golgi membranes to increase LRRK2 kinase activity, there is little evidence that endogenous Rab29 performs this function under physiological conditions. Here we identify Rab38 as a novel physiological regulator of LRRK2. In mouse melanocytes, which express high levels of Rab38, Rab32, and Rab29, knockdown of Rab38 but not Rab32 or Rab29 decreases phosphorylation of multiple LRRK2 substrates, including Rab10 and Rab12, by both exogenous and endogenous LRRK2. In B16-F10 mouse melanoma cells, Rab38 drives LRRK2 membrane association, and overexpressed kinase-active but not kinase-inactive LRRK2 shows striking pericentriolar recruitment, which is dependent on the presence of endogenous Rab38 but not Rab32 or Rab29. Deletion or mutation of LRRK2 at the Rab38 binding site in the N-terminal armadillo domain decreases LRRK2 membrane association, pericentriolar recruitment, and ability to phosphorylate Rab10. Consistently, overexpression of LRRK2 350-550, a fragment that encompasses the Rab38 binding site, blocks endogenous LRRK2's phosphorylation of Thr73-Rab10. Finally, disruption of BLOC-3, the guanine nucleotide exchange factor for Rab38 and 32, inhibits Rab38's regulation of LRRK2. In sum, our data identify Rab38 as a physiologic regulator of LRRK2 function and lend support to a model in which LRRK2 plays a central role in Rab GTPase coordination of vesicular trafficking.

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The development of inhibitors of leucine‐rich repeat kinase 2 (LRRK2) as a therapeutic strategy for Parkinson's disease: the current state of play

Cited by 44 publications

References 152 publications

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Structural basis for the specificity of PPM1H phosphatase for Rab GTPases

Endogenous Rab38 regulates LRRK2’s membrane recruitment and substrate Rab phosphorylation in melanocytes

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