Molecular Pathways Involved in LRRK2-Linked Parkinson’s Disease: A Systematic Review

Ravinther, Ailyn Irvita; Dewadas, Hemaniswarri Dewi; Tong, Shi; Foo, Chai Nien; Lin, Yan; Chien, Cheng-Ting; Lim, Yang Mooi

doi:10.3390/ijms231911744

Cited by 8 publications

(7 citation statements)

References 140 publications

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“…The LRRK2 gene encodes the protein leucine-rich repeat kinase 2 (LRRK2), a large (288 kDa) multimeric protein in the Roco family [35,36]. LRRK2 has three protein-interactive domains towards its Nterminus: armadillo, ankyrin, and leucine-rich repeat motifs.…”

Section: Lrrk2 Structure and Functionmentioning

confidence: 99%

How Parkinson’s Disease-Linked LRRK2 Mutations Affect Different CNS Cell Types

Bailey,

Cookson

2024

JPD

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LRRK2 is a relatively common genetic risk factor for Parkinson’s disease (PD), with six coding variants known to cause familial PD. Non-coding variation at the same locus is also associated with sporadic PD. LRRK2 plays a role in many different intracellular signaling cascades including those involved in endolysosomal function, cytoskeletal dynamics, and Ca2+ homeostasis. PD-causing LRRK2 mutations cause hyperactive LRRK2 kinase activity, resulting in altered cellular signaling. Importantly, LRRK2 is lowly expressed in neurons and prominently expressed in non-neuronal cells in the brain. In this review, we will summarize recent and novel findings on the effects of PD-causing LRRK2 mutations in different nervous system cell types. This review will also provide novel insight into future areas of research at the intersection of LRRK2 cell biology, cell type specificity, and PD.

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Section: Lrrk2 Structure and Functionmentioning

confidence: 99%

How Parkinson’s Disease-Linked LRRK2 Mutations Affect Different CNS Cell Types

Bailey,

Cookson

2024

JPD

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“…Despite the molecular and cell biological similarities between LRRK1 and LRRK2, the proteins are strikingly different in their disease association. All the most common PD-linked mutations in LRRK2 are autosomal dominant gain-of-function mutations that activate its kinase 10 . LRRK2 has also been linked to Crohn's disease and leprosy 11,12 .…”

Section: Cryo-em Structure Of Monomeric Lrrk1mentioning

confidence: 99%

“…Our structural and mechanistic understanding of LRRK2 has expanded substantially over the past few years, with several structures of the protein now available [14][15][16][17] , along with insights into LRRK2's cellular localization 18 , substrates [6][7][8] and regulation 10 . This level of knowledge is missing for LRRK1, for which only low-resolution structures have been reported for the full-length protein 19 .…”

Section: Cryo-em Structure Of Monomeric Lrrk1mentioning

confidence: 99%

Structure of LRRK1 and mechanisms of autoinhibition and activation

Reimer,

Dickey,

Lin

et al. 2023

Nat Struct Mol Biol

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Leucine Rich Repeat Kinase 1 and 2 (LRRK1 and LRRK2) are homologs in the ROCO family of proteins in humans. Despite their shared domain architecture and involvement in intracellular trafficking, their disease associations are strikingly different: LRRK2 is involved in familial Parkinson’s disease while LRRK1 is linked to bone diseases. Furthermore, Parkinson’s disease-linked mutations in LRRK2 are typically autosomal dominant gain-of-function while those in LRRK1 are autosomal recessive loss-of-function. Here, to understand these differences, we solved cryo-EM structures of LRRK1 in its monomeric and dimeric forms. Both differ from the corresponding LRRK2 structures. Unlike LRRK2, which is sterically autoinhibited as a monomer, LRRK1 is sterically autoinhibited in a dimer-dependent manner. LRRK1 has an additional level of autoinhibition that prevents activation of the kinase and is absent in LRRK2. Finally, we place the structural signatures of LRRK1 and LRRK2 in the context of the evolution of the LRRK family of proteins.

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“…While much is yet to be learned about LRRK2, our structural and mechanistic understanding of it has expanded significantly over the last few years, with several structures of the protein now available (Deniston et al, 2020;Myasnikov et al, 2021;Snead et al, 2022;Watanabe et al, 2020), along with insights into LRRK2's cellular localization (Usmani et al, 2021), substrates (Malik et al, 2021;Steger et al, 2017Steger et al, , 2016, and regulation (Ravinther et al, 2022). This level of knowledge is missing for LRRK1.…”

Section: Introductionmentioning

confidence: 99%

“…Despite the molecular and cell biological similarities between LRRK1 and LRRK2, the proteins are strikingly different when it comes to their disease association. LRRK2 is well known for its involvement in Parkinson’s Disease; all the most common PD-linked mutations in LRRK2 are autosomal dominant gain-of-function mutations that activate its kinase (Ravinther et al, 2022). LRRK2 has also been linked to Crohn’s disease and leprosy (Hui et al, 2018; Schurr and Gros, 2009).…”

Section: Introductionmentioning

confidence: 99%

Structure of LRRK1 and mechanisms of autoinhibition and activation

Reimer

Dickey

Lin

et al. 2022

Preprint

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Leucine Rich Repeat Kinase 1 and 2 (LRRK1 and LRRK2) are homologs in the ROCO family of proteins in humans. Despite their shared domain architecture and involvement in intracellular trafficking, their disease associations are strikingly different: LRRK2 is involved in familial Parkinson's Disease (PD) while LRRK1 is linked to bone diseases. Furthermore, PD-linked mutations in LRRK2 are typically autosomal dominant gain-of-function while those in LRRK1 are autosomal recessive loss-of-function. To understand these differences, we solved cryo-EM structures of LRRK1 in its monomeric and dimeric forms. Both differ from the corresponding LRRK2 structures. Unlike LRRK2, which is sterically autoinhibited as a monomer, LRRK1 is sterically autoinhibited in a dimer-dependent manner. LRRK1 has an additional level of autoinhibition that prevents activation of the kinase and is absent in LRRK2. Finally, we place the structural signatures of LRRK1 and LRRK2 in the context of the evolution of the LRRK family of proteins.

show abstract

Molecular Pathways Involved in LRRK2-Linked Parkinson’s Disease: A Systematic Review

Cited by 8 publications

References 140 publications

How Parkinson’s Disease-Linked LRRK2 Mutations Affect Different CNS Cell Types

How Parkinson’s Disease-Linked LRRK2 Mutations Affect Different CNS Cell Types

Structure of LRRK1 and mechanisms of autoinhibition and activation

Structure of LRRK1 and mechanisms of autoinhibition and activation

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