A novel rare variant of LRRK2 associated with familial Parkinson's disease: p.R1501W

Masuzugawa, Satoshi; Nishioka, Kenya; Imai, Yuzuru; Ogata, Jun; Shojima, Yuri; Li, Yuanzhe; Yoshino, Hideaki

doi:10.1016/j.parkreldis.2020.05.035

Cited by 5 publications

(3 citation statements)

References 5 publications

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“…Although none of the most common PD-linked mutations in LRRK2 are found in these basic-patch regions, the recently reported p.R1501W variant 57 is found in the ROC domain facing the microtubule, near the basic patches we identified (Fig. 5c ).…”

Section: Resultsmentioning

confidence: 52%

Structural basis for Parkinson’s disease-linked LRRK2’s binding to microtubules

Snead

Matyszewski

Dickey

et al. 2022

Nat Struct Mol Biol

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Leucine-rich repeat kinase 2 (LRRK2) is one of the most commonly mutated genes in familial Parkinson’s disease (PD). Under some circumstances, LRRK2 co-localizes with microtubules in cells, an association enhanced by PD mutations. We report a cryo-EM structure of the catalytic half of LRRK2, containing its kinase, in a closed conformation, and GTPase domains, bound to microtubules. We also report a structure of the catalytic half of LRRK1, which is closely related to LRRK2 but is not linked to PD. Although LRRK1’s structure is similar to that of LRRK2, we find that LRRK1 does not interact with microtubules. Guided by these structures, we identify amino acids in LRRK2’s GTPase that mediate microtubule binding; mutating them disrupts microtubule binding in vitro and in cells, without affecting LRRK2’s kinase activity. Our results have implications for the design of therapeutic LRRK2 kinase inhibitors.

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Section: Resultsmentioning

confidence: 52%

Structural basis for Parkinson’s disease-linked LRRK2’s binding to microtubules

Snead

Matyszewski

Dickey

et al. 2022

Nat Struct Mol Biol

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“…We discovered that mutating two basic amino acids in LRRK2's ROC domain was sufficient to block microtubule binding both in cells and in vitro. We also showed that a PDlinked variant (R1501W) 51 , which is located in the same region of the ROC domain, decreased microtubule binding in cells. Together, this work provides important insights and tools for probing the cellular function and localization of LRRK2 and for designing LRRK2-specific kinase inhibitors.…”

Section: Discussionmentioning

confidence: 59%

Structural basis for Parkinson’s Disease-linked LRRK2’s binding to microtubules

Snead

Matyszewski

Dickey

et al. 2022

Preprint

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Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most commonly mutated genes in familial Parkinson's Disease (PD). Under some circumstances, LRRK2 co-localizes with microtubules in cells, an association enhanced by PD mutations. We report a cryo-electron microscopy structure of the catalytic half of LRRK2, containing its kinase, which is in a closed conformation, and GTPase domains, bound to microtubules. We also report a structure of the catalytic half of LRRK1, which is closely related to LRRK2, but is not linked to PD. LRRK1's structure is similar to LRRK2, but LRRK1 does not interact with microtubules. Guided by these structures, we identify amino acids in LRRK2's GTPase domain that mediate microtubule binding; mutating them disrupts microtubule binding in vitro and in cells, without affecting LRRK2's kinase activity. Our results have implications for the design of therapeutic LRRK2 kinase inhibitors.

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“…Though elevated LRRK2 activity in PD is suggested to be involved in exacerbated immune response, other functions such as the lysosomal stress response, synaptic vesicle recycling in DA neurons and changes in trophic support of DA neurons may also be impacted [ 56 ]. It is also likely that other pathological mechanisms may exist in addition to the increased kinase activity [ 57 ]. The LRRK2 inhibitors (DNL201 and DNL151) developed by Denali Therapeutics seem to be designed specifically with the aim of restoring the LRRK-mediated lysosomal dysfunction in PD as stated in a Press release ( https://www.globenewswire.com/news-release/2020/01/14/1970308/0/en/...sitive-Results-From-Its-LRRK2-Program-for-Parkinson-s-Disease.html ), at the Denali-Therapeutics website ( https://www.denalitherapeutics.com/pipeline ), and the Denali Therapeutics’ January 2020 report ( https://denalitherapeutics.gcs-web.com/node/7361/pdf ).…”

Section: Introductionmentioning

confidence: 99%

Precision medicine in Parkinson’s disease patients with LRRK2 and GBA risk variants – Let’s get even more personal

Linstow

Gan‐Or

Brundin

2020

Transl Neurodegener

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Parkinson’s disease (PD) is characterized by motor deficits and a wide variety of non-motor symptoms. The age of onset, rate of disease progression and the precise profile of motor and non-motor symptoms display considerable individual variation. Neuropathologically, the loss of substantia nigra dopaminergic neurons is a key feature of PD. The vast majority of PD patients exhibit alpha-synuclein aggregates in several brain regions, but there is also great variability in the neuropathology between individuals. While the dopamine replacement therapies can reduce motor symptoms, current therapies do not modify the disease progression. Numerous clinical trials using a wide variety of approaches have failed to achieve disease modification. It has been suggested that the heterogeneity of PD is a major contributing factor to the failure of disease modification trials, and that it is unlikely that a single treatment will be effective in all patients. Precision medicine, using drugs designed to target the pathophysiology in a manner that is specific to each individual with PD, has been suggested as a way forward. PD patients can be stratified according to whether they carry one of the risk variants associated with elevated PD risk. In this review we assess current clinical trials targeting two enzymes, leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA), which are encoded by two most common PD risk genes. Because the details of the pathogenic processes coupled to the different LRRK2 and GBA risk variants are not fully understood, we ask if these precision medicine-based intervention strategies will prove “precise” or “personalized” enough to modify the disease process in PD patients. We also consider at what phases of the disease that such strategies might be effective, in light of the genes being primarily associated with the risk of developing disease in the first place, and less clearly linked to the rate of disease progression. Finally, we critically evaluate the notion that therapies targeting LRRK2 and GBA might be relevant to a wider segment of PD patients, beyond those that actually carry risk variants of these genes.

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A novel rare variant of LRRK2 associated with familial Parkinson's disease: p.R1501W

Cited by 5 publications

References 5 publications

Structural basis for Parkinson’s disease-linked LRRK2’s binding to microtubules

Structural basis for Parkinson’s disease-linked LRRK2’s binding to microtubules

Structural basis for Parkinson’s Disease-linked LRRK2’s binding to microtubules

Precision medicine in Parkinson’s disease patients with LRRK2 and GBA risk variants – Let’s get even more personal

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