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Biomolecules
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Pathological Roles of LRRK2
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Pathological Roles of LRRK2

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (15 December 2023) | Viewed by 17314

Special Issue Editor

Dr. Genta Ito

E-Mail Website
Guest Editor
Faculty of Pharma-Science, Teikyo University, Tokyo, Japan
Interests: LRRK2; Rab GTPase; phosphorylation; Parkinson disease; trafficking

Special Issue Information

Dear Colleagues,

Leucine-rich repeat kinase 2 (LRRK2) is a multidomain Ser/Thr kinase that physiologically phosphorylates several substrate proteins, including Rab GTPases, which are molecular switches for intracellular vesicular transport. LRRK2 has been identified as a gene associated with familial and sporadic Parkinson disease (PD), and recent studies suggest that its overactivation is involved in the pathogenic process of PD. LRRK2 has also been found to be associated with several immunological disorders, namely, inflammatory bowel diseases, including Crohn disease and ulcerative colitis, Hansen disease (leprosy), and systemic lupus erythematosus; however, the pathological significance of substrate phosphorylation in the context of these diseases remains unclear. 

This Special Issue of Biomolecules focuses on recent advances relating to the pathological roles of LRRK2 in diseases, including those listed above. It highlights original studies that biochemically or cell biologically address the biological and pathological roles of LRRK2 in vitro and in cultured cells, as well as studies that examine the importance of LRRK2 in vivo. As LRRK2 is highly expressed in brain cells (neuronal and non-neuronal), immune cells and other disease-associated cells, the discussion of how LRRK2 causes disease in these cells will also be encouraged. Review articles that summarize the latest literature and provide an overview of relevant topics are also welcome.

Dr. Genta Ito
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • leucine-rich repeat kinase 2 (LRRK2)
  • rab
  • phosphorylation
  • parkinson disease
  • inflammatory bowel diseases
  • crohn disease
  • ulcerative colitis
  • hansen disease
  • leprosy
  • systemic lupus erythematosus

Published Papers (7 papers)

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Research

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10 pages, 1616 KiB  
Article
Age- and Sex-Dependent Behavioral and Neurochemical Alterations in hLRRK2-G2019S BAC Mice
by Ning Yao, Olga Skiteva and Karima Chergui
Biomolecules 2023, 13(1), 51; https://doi.org/10.3390/biom13010051 - 27 Dec 2022
Cited by 1 | Viewed by 1407
Abstract
The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is associated with late-onset Parkinson’s disease (PD). Although PD affects men and women differently, longitudinal studies examining sex- and age-dependent alterations in mice carrying the G2019S mutation are limited. We [...] Read more.
The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is associated with late-onset Parkinson’s disease (PD). Although PD affects men and women differently, longitudinal studies examining sex- and age-dependent alterations in mice carrying the G2019S mutation are limited. We examined if behavioral and neurochemical dysfunctions, as well as neurodegeneration, occur in male and female BAC LRRK2-hG2019S (G2019S) mice, compared to their age-matched wild type littermates, at four age ranges. In the open field test, hyperlocomotion was observed in 10–12 month old male and 2–4.5 months old female G2019S mice. In the pole test, motor coordination was impaired in male G2019S mice from 15 months of age and in 20–21 months old female G2019S mice. In the striatum of G2019S male and female mice, the amounts of tyrosine hydroxylase (TH), measured with Western blotting, were unaltered. However, we found a decreased expression of the dopamine transporter in 20–21 month old male G2019S mice. The number of TH-positive neurons in the substantia nigra compacta was unaltered in 20–21 month old male and female G2019S mice. These results identify sex- and age-dependent differences in the occurrence of motor and neurochemical deficits in BAC LRRK2-hG2019S mice, and no degeneration of DA neurons. Full article
(This article belongs to the Special Issue Pathological Roles of LRRK2)
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10 pages, 1332 KiB  
Article
Neuronal Firing and Glutamatergic Synapses in the Substantia Nigra Pars Reticulata of LRRK2-G2019S Mice
by Giacomo Sitzia, Olga Skiteva and Karima Chergui
Biomolecules 2022, 12(11), 1635; https://doi.org/10.3390/biom12111635 - 04 Nov 2022
Cited by 1 | Viewed by 1715
Abstract
Pathogenic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are frequent causes of familial Parkinson’s Disease (PD), an increasingly prevalent neurodegenerative disease that affects basal ganglia circuitry. The cellular effects of the G2019S mutation in the LRRK2 gene, the most [...] Read more.
Pathogenic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are frequent causes of familial Parkinson’s Disease (PD), an increasingly prevalent neurodegenerative disease that affects basal ganglia circuitry. The cellular effects of the G2019S mutation in the LRRK2 gene, the most common pathological mutation, have not been thoroughly investigated. In this study we used middle-aged mice carrying the LRRK2-G2019S mutation (G2019S mice) to identify potential alterations in the neurophysiological properties and characteristics of glutamatergic synaptic transmission in basal ganglia output neurons, i.e., substantia nigra pars reticulata (SNr) GABAergic neurons. We found that the intrinsic membrane properties and action potential properties were unaltered in G2019S mice compared to wild-type (WT) mice. The spontaneous firing frequency was similar, but we observed an increased regularity in the firing of SNr neurons recorded from G2019S mice. We examined the short-term plasticity of glutamatergic synaptic transmission, and we found an increased paired-pulse depression in G2019S mice compared to WT mice, indicating an increased probability of glutamate release in SNr neurons from G2019S mice. We measured synaptic transmission mediated by NMDA receptors and we found that the kinetics of synaptic responses mediated by these receptors were unaltered, as well as the contribution of the GluN2B subunit to these responses, in SNr neurons of G2019S mice compared to WT mice. These results demonstrate an overall maintenance of basic neurophysiological and synaptic characteristics, and subtle changes in the firing pattern and in glutamatergic synaptic transmission in basal ganglia output neurons that precede neurodegeneration of dopaminergic neurons in the LRRK2-G2019S mouse model of late-onset PD. Full article
(This article belongs to the Special Issue Pathological Roles of LRRK2)
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Review

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19 pages, 1587 KiB  
Review
An Update on the Interplay between LRRK2, Rab GTPases and Parkinson’s Disease
by Tadayuki Komori and Tomoki Kuwahara
Biomolecules 2023, 13(11), 1645; https://doi.org/10.3390/biom13111645 - 13 Nov 2023
Viewed by 1533
Abstract
Over the last decades, research on the pathobiology of neurodegenerative diseases has greatly evolved, revealing potential targets and mechanisms linked to their pathogenesis. Parkinson’s disease (PD) is no exception, and recent studies point to the involvement of endolysosomal defects in PD. The endolysosomal [...] Read more.
Over the last decades, research on the pathobiology of neurodegenerative diseases has greatly evolved, revealing potential targets and mechanisms linked to their pathogenesis. Parkinson’s disease (PD) is no exception, and recent studies point to the involvement of endolysosomal defects in PD. The endolysosomal system, which tightly controls a flow of endocytosed vesicles targeted either for degradation or recycling, is regulated by a number of Rab GTPases. Their associations with leucine-rich repeat kinase 2 (LRRK2), a major causative and risk protein of PD, has also been one of the hot topics in the field. Understanding their interactions and functions is critical for unraveling their contribution to PD pathogenesis. In this review, we summarize recent studies on LRRK2 and Rab GTPases and attempt to provide more insight into the interaction of LRRK2 with each Rab and its relationship to PD. Full article
(This article belongs to the Special Issue Pathological Roles of LRRK2)
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24 pages, 3538 KiB  
Review
Overview of the Impact of Pathogenic LRRK2 Mutations in Parkinson’s Disease
by Genta Ito and Naoko Utsunomiya-Tate
Biomolecules 2023, 13(5), 845; https://doi.org/10.3390/biom13050845 - 16 May 2023
Cited by 1 | Viewed by 2517
Abstract
Leucine-rich repeat kinase 2 (LRRK2) is a large protein kinase that physiologically phosphorylates and regulates the function of several Rab proteins. LRRK2 is genetically implicated in the pathogenesis of both familial and sporadic Parkinson’s disease (PD), although the underlying mechanism is not well [...] Read more.
Leucine-rich repeat kinase 2 (LRRK2) is a large protein kinase that physiologically phosphorylates and regulates the function of several Rab proteins. LRRK2 is genetically implicated in the pathogenesis of both familial and sporadic Parkinson’s disease (PD), although the underlying mechanism is not well understood. Several pathogenic mutations in the LRRK2 gene have been identified, and in most cases the clinical symptoms that PD patients with LRRK2 mutations develop are indistinguishable from those of typical PD. However, it has been shown that the pathological manifestations in the brains of PD patients with LRRK2 mutations are remarkably variable when compared to sporadic PD, ranging from typical PD pathology with Lewy bodies to nigral degeneration with deposition of other amyloidogenic proteins. The pathogenic mutations in LRRK2 are also known to affect the functions and structure of LRRK2, the differences in which may be partly attributable to the variations observed in patient pathology. In this review, in order to help researchers unfamiliar with the field to understand the mechanism of pathogenesis of LRRK2-associated PD, we summarize the clinical and pathological manifestations caused by pathogenic mutations in LRRK2, their impact on the molecular function and structure of LRRK2, and their historical background. Full article
(This article belongs to the Special Issue Pathological Roles of LRRK2)
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15 pages, 1822 KiB  
Review
Is Glial Dysfunction the Key Pathogenesis of LRRK2-Linked Parkinson’s Disease?
by Tatou Iseki, Yuzuru Imai and Nobutaka Hattori
Biomolecules 2023, 13(1), 178; https://doi.org/10.3390/biom13010178 - 15 Jan 2023
Cited by 5 | Viewed by 2943
Abstract
Leucine rich-repeat kinase 2 (LRRK2) is the most well-known etiologic gene for familial Parkinson’s disease (PD). Its gene product is a large kinase with multiple functional domains that phosphorylates a subset of Rab small GTPases. However, studies of autopsy cases with [...] Read more.
Leucine rich-repeat kinase 2 (LRRK2) is the most well-known etiologic gene for familial Parkinson’s disease (PD). Its gene product is a large kinase with multiple functional domains that phosphorylates a subset of Rab small GTPases. However, studies of autopsy cases with LRRK2 mutations indicate a varied pathology, and the molecular functions of LRRK2 and its relationship to PD pathogenesis are largely unknown. Recently, non-autonomous neurodegeneration associated with glial cell dysfunction has attracted attention as a possible mechanism of dopaminergic neurodegeneration. Molecular studies of LRRK2 in astrocytes and microglia have also suggested that LRRK2 is involved in the regulation of lysosomal and other organelle dynamics and inflammation. In this review, we describe the proposed functions of LRRK2 in glial cells and discuss its involvement in the pathomechanisms of PD. Full article
(This article belongs to the Special Issue Pathological Roles of LRRK2)
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11 pages, 1618 KiB  
Review
Advances in Gene Therapy Techniques to Treat LRRK2 Gene Mutation
by Sun-Ku Chung and Seo-Young Lee
Biomolecules 2022, 12(12), 1814; https://doi.org/10.3390/biom12121814 - 05 Dec 2022
Cited by 2 | Viewed by 2365
Abstract
Leucine-rich repeat kinase 2 (LRRK2) gene mutation is an autosomal dominant mutation associated with Parkinson’s disease (PD). Among LRRK2 gene mutations, the LRRK2 G2019S mutation is frequently involved in PD onset. Currently, diverse gene correction tools such as zinc finger nucleases [...] Read more.
Leucine-rich repeat kinase 2 (LRRK2) gene mutation is an autosomal dominant mutation associated with Parkinson’s disease (PD). Among LRRK2 gene mutations, the LRRK2 G2019S mutation is frequently involved in PD onset. Currently, diverse gene correction tools such as zinc finger nucleases (ZFNs), helper-dependent adenoviral vector (HDAdV), the bacterial artificial chromosome-based homologous recombination (BAC-based HR) system, and CRISPR/Cas9-homology-directed repair (HDR) or adenine base editor (ABE) are used in genome editing. Gene correction of the LRRK2 G2019S mutation has been applied whenever new gene therapy tools emerge, being mainly applied to induced pluripotent stem cells (LRRK2 G2019S-mutant iPSCs). Here, we comprehensively introduce the principles and methods of each programmable nuclease such as ZFN, CRISPR/Cas9-HDR or ABE applied to LRRK2 G2019S, as well as those of HDAdV or BAC-based HR systems used as nonprogrammable nuclease systems. Full article
(This article belongs to the Special Issue Pathological Roles of LRRK2)
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18 pages, 1592 KiB  
Review
LRRK2 and Lipid Pathways: Implications for Parkinson’s Disease
by Jasmin Galper, Woojin S. Kim and Nicolas Dzamko
Biomolecules 2022, 12(11), 1597; https://doi.org/10.3390/biom12111597 - 30 Oct 2022
Cited by 5 | Viewed by 3828
Abstract
Genetic alterations in the LRRK2 gene, encoding leucine-rich repeat kinase 2, are a common risk factor for Parkinson’s disease. How LRRK2 alterations lead to cell pathology is an area of ongoing investigation, however, multiple lines of evidence suggest a role for LRRK2 in [...] Read more.
Genetic alterations in the LRRK2 gene, encoding leucine-rich repeat kinase 2, are a common risk factor for Parkinson’s disease. How LRRK2 alterations lead to cell pathology is an area of ongoing investigation, however, multiple lines of evidence suggest a role for LRRK2 in lipid pathways. It is increasingly recognized that in addition to being energy reservoirs and structural entities, some lipids, including neural lipids, participate in signaling cascades. Early investigations revealed that LRRK2 localized to membranous and vesicular structures, suggesting an interaction of LRRK2 and lipids or lipid-associated proteins. LRRK2 substrates from the Rab GTPase family play a critical role in vesicle trafficking, lipid metabolism and lipid storage, all processes which rely on lipid dynamics. In addition, LRRK2 is associated with the phosphorylation and activity of enzymes that catabolize plasma membrane and lysosomal lipids. Furthermore, LRRK2 knockout studies have revealed that blood, brain and urine exhibit lipid level changes, including alterations to sterols, sphingolipids and phospholipids, respectively. In human LRRK2 mutation carriers, changes to sterols, sphingolipids, phospholipids, fatty acyls and glycerolipids are reported in multiple tissues. This review summarizes the evidence regarding associations between LRRK2 and lipids, and the functional consequences of LRRK2-associated lipid changes are discussed. Full article
(This article belongs to the Special Issue Pathological Roles of LRRK2)
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