Closing the structure-to-function gap for LRRK2

Tokars, Valerie; Chen, Chuyu; Parisiadou, Loukia

doi:10.1016/j.tibs.2021.10.003

Cited by 5 publications

(5 citation statements)

References 10 publications

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“…These two mutations are located in the kinase and ROC (Ras of complex GTPase) domains of the LRRK2 protein, respectively (Fig. 1a) 12 . Although it is widely accepted that all pathogenic mutations increase LRRK2 kinase activity 13,14 , the mechanism through which LRRK2 leads to the disease neuropathology remains unclear.…”

Section: Mainmentioning

confidence: 99%

R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations

et al. 2022

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LRRK2 mutations are closely associated with Parkinson’s disease (PD). Convergent evidence suggests that LRRK2 regulates striatal function. Here, by using knock-in mouse lines expressing the two most common LRRK2 pathogenic mutations—G2019S and R1441C—we investigated how LRRK2 mutations altered striatal physiology. While we found that both R1441C and G2019S mice displayed reduced nigrostriatal dopamine release, hypoexcitability in indirect-pathway striatal projection neurons, and alterations associated with an impaired striatal-dependent motor learning were observed only in the R1441C mice. We also showed that increased synaptic PKA activities in the R1441C and not G2019S mice underlie the specific alterations in motor learning deficits in the R1441C mice. In summary, our data argue that LRRK2 mutations’ impact on the striatum cannot be simply generalized. Instead, alterations in electrochemical, electrophysiological, molecular, and behavioral levels were distinct between LRRK2 mutations. Our findings offer mechanistic insights for devising and optimizing treatment strategies for PD patients.

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Section: Mainmentioning

confidence: 99%

R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations

et al. 2022

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“…Therefore, there is an urgent need for high-resolution LRRK2 structures to facilitate a deep understanding of the functions of individual domains. In the past few years, the high-resolution structures of LRRK2 protein have been successfully revealed, by using a combination of in vitro and in situ techniques ( Deniston et al, 2020 ; Watanabe et al, 2020 ; Myasnikov et al, 2021 ; Tokars et al, 2021 ; Ullrich, 2021 ). Specifically, Weng et al (2022) generated a comprehensive dynamic allosteric map of the C-terminal domain of LRRK2 (LRRK2RCKW) using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics (MD) simulations, while confirming that the kinase domain is a central hub for conformational control.…”

Section: Leucine-rich Repeat Kinase 2: Structure and Role In The Immu...mentioning

confidence: 99%

“…It is well-established that LRRK2 has three quaternary structures: monomer, dimer, and oligomer, which were found to display different biological activities. Tokars et al (2021) cracked the structure of LRRK2 monomer, dimer and mutant G2019S based on the high-resolution structure of the full-length human LRRK2, and thus explained the internal structure, assembly and activity regulation mechanism of LRRK2. Myasnikov et al (2021) further confirmed that COR-mediated single point mutations at the LRRK2 dimer interface can eliminate the pathogenic filaments formed by LRRK2.…”

Section: Leucine-rich Repeat Kinase 2: Structure and Role In The Immu...mentioning

confidence: 99%

The Double-Faceted Role of Leucine-Rich Repeat Kinase 2 in the Immunopathogenesis of Parkinson’s Disease

Zhang

Ren

et al. 2022

Front. Aging Neurosci.

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Leucine-rich repeat kinase 2 (LRRK2) is one of the most common causative genes in Parkinson’s disease (PD). The complex structure of this multiple domains’ protein determines its versatile functions in multiple physiological processes, including migration, autophagy, phagocytosis, and mitochondrial function, among others. Mounting studies have also demonstrated the role of LRRK2 in mediating neuroinflammation, the prominent hallmark of PD, and intricate functions in immune cells, such as microglia, macrophages, and astrocytes. Of those, microglia were extensively studied in PD, which serves as the resident immune cell of the central nervous system that is rapidly activated upon neuronal injury and pathogenic insult. Moreover, the activation and function of immune cells can be achieved by modulating their intracellular metabolic profiles, in which LRRK2 plays an emerging role. Here, we provide an updated review focusing on the double-faceted role of LRRK2 in regulating various cellular physiology and immune functions especially in microglia. Moreover, we will summarize the latest discovery of the three-dimensional structure of LRRK2, as well as the function and dysfunction of LRRK2 in immune cell-related pathways.

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“…PD is a disorder characterized by the loss of the nigrostriatal dopamine neurons, which results in significant motor deficits. Variants of several genes have been linked to familial PD, with the kinase LRRK2 being particularly interesting due to its association with both familial and idiopathic PD 17 , 18 , 19 . Previous studies have found that, in the striatum, LRRK2 is highly expressed in SPNs and plays a crucial role in regulating the striatal function 20 , 22 , 22 , 23 , 24 , 25 , 26 including via modulation of D2R signaling 27 - 29 .…”

Section: Introductionmentioning

confidence: 99%

LRRK2 mediates haloperidol-induced changes in indirect pathway striatal projection neurons

Chen,

Masotti,

Shepard

et al. 2024

Preprint

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Haloperidol is used to manage psychotic symptoms in several neurological disorders through mechanisms that involve antagonism of dopamine D2 receptors that are highly expressed in the striatum. Significant side effects of haloperidol, known as extrapyramidal symptoms, lead to motor deficits similar to those seen in Parkinson’s disease and present a major challenge in clinical settings. The underlying molecular mechanisms responsible for these side effects remain poorly understood. Parkinson’s disease-associated LRRK2 kinase has an important role in striatal physiology and a known link to dopamine D2 receptor signaling. Here, we systematically explore convergent signaling of haloperidol and LRRK2 through pharmacological or genetic inhibition of LRRK2 kinase, as well as knock-in mouse models expressing pathogenic mutant LRRK2 with increased kinase activity. Behavioral assays show that LRRK2 kinase inhibition ameliorates haloperidol-induced motor changes in mice. A combination of electrophysiological and anatomical approaches reveals that LRRK2 kinase inhibition interferes with haloperidol-induced changes, specifically in striatal neurons of the indirect pathway. Proteomic studies and targeted intracellular pathway analyses demonstrate that haloperidol induces a similar pattern of intracellular signaling as increased LRRK2 kinase activity. Our study suggests that LRRK2 kinase plays a key role in striatal dopamine D2 receptor signaling underlying the undesirable motor side effects of haloperidol. This work opens up new therapeutic avenues for dopamine-related disorders, such as psychosis, also furthering our understanding of Parkinson’s disease pathophysiology.SummaryChen et al. demonstrate that haloperidol mediated changes in the striatal indirect pathway neurons and circuits are linked to Parkinson’s disease associated LRRK2. Inhibiting LRRK2 kinase activity ameliorates the motoric side effects of haloperidol, suggesting a potential approach to alleviating the unwanted side effects of antipsychotics.

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Closing the structure-to-function gap for LRRK2

Cited by 5 publications

References 10 publications

R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations

R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations

The Double-Faceted Role of Leucine-Rich Repeat Kinase 2 in the Immunopathogenesis of Parkinson’s Disease

LRRK2 mediates haloperidol-induced changes in indirect pathway striatal projection neurons

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