Special Issue "LRRK2-Dependent Neurodegeneration in Parkinson’s Disease"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: closed (30 September 2020).

Special Issue Editor

Dr. Michele Morari
E-Mail Website
Guest Editor
Department of Neuroscience and Rehabilitation, Section of Pharmacology, University of Ferrara, Via Fossato di Mortara 17-19, 44122 Ferrara, Italy
Interests: movement disorders; Parkinson’s disease; levodopa-induced dyskinesia; basal ganglia; neurotransmitter release; LRRK2; autophagy; dopamine; glutamate; opioids; nociceptin/orphanin FQ; MAO-B inhibitors

Special Issue Information

Dear Colleagues,

Parkinson’s disease is the second most common neurodegenerative disorder, affecting more than 10 million people worldwide. Parkinson’s disease has a complex etiology, with genetic factors playing a significant role not only in familiar, monogenic forms but also in idiopathic condition. Mutations in LRRK2 have been recognized as the most common genetic cause of familial Parkinson’s disease, and LRRK2 itself is considered a risk factor in idiopathic Parkinson’s disease. LRRK2 is a large multidomain protein with a GTPase and kinase catalytic core surrounded by protein–protein interaction domains. LRRK2 regulates several cellular functions, including vesicle trafficking, cytoskeletal dynamics, neurotransmitter release, synaptic plasticity, mitochondrial function, autophagy, and immune response. All of these functions are dysregulated in Parkinson’s disease, suggesting LRRK2 may play a direct or indirect role. Indeed, preclinical studies have revealed that pathogenic LRRK2 mutations, notably the p.G2019S substitution at the kinase domain, favor the degeneration of nigrostriatal dopaminergic neurons and formation of alpha-synuclein inclusions, which are neuropathological hallmarks of the disease. The enhancement of kinase activity proved to be instrumental for LRRK2-mediated neurodegeneration, leading to the development of LRRK2 kinase inhibitors as possible disease-modifying agents in Parkinson’s disease. In recognition of the intense and ever-growing research in the field, as well as the clinical relevance of this topic, this Special Issue welcomes original papers and up-to-date reviews dealing with the mechanisms underlying the contribution of LRRK2 to the neurodegeneration associated with Parkinson’s disease.

Prof. Michele Morari
Guest Editor

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Keywords

  • Parkinson’s disease
  • LRRK2
  • aging
  • synucleinopathy
  • proteostasis
  • alpha-synuclein
  • autophagy
  • mitophagy
  • microglia
  • parkin
  • PINK1
  • neuroinflammation
  • vesicle trafficking
  • LRRK2 kinase inhibitors
  • Rab

Published Papers (8 papers)

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Research

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Article
A LRRK2 GTP Binding Inhibitor, 68, Reduces LPS-Induced Signaling Events and TNF-α Release in Human Lymphoblasts
Cells 2021, 10(2), 480; https://doi.org/10.3390/cells10020480 - 23 Feb 2021
Cited by 1 | Viewed by 915
Abstract
Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant Parkinson’s disease (PD) and contribute to sporadic PD. Common genetic variation in LRRK2 modifies susceptibility to immunological disorders including Crohn’s disease and leprosy. Previous studies have reported that LRRK2 is expressed in B [...] Read more.
Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant Parkinson’s disease (PD) and contribute to sporadic PD. Common genetic variation in LRRK2 modifies susceptibility to immunological disorders including Crohn’s disease and leprosy. Previous studies have reported that LRRK2 is expressed in B lymphocytes and macrophages, suggesting a role for LRRK2 in immunological functions. In this study, we characterized the LRRK2 protein expression and phosphorylation using human lymphoblasts. Lipopolysaccharide (LPS), a proinflammatory agent, induced the increase of LRRK2 expression and kinase activities in human lymphoblasts in a time-dependent manner. Moreover, LPS activated the Toll-like receptor (TLR) signaling pathway, increased TRAF6/LRRK2 interaction, and elevated the phosphorylation levels of MAPK (JNK1/2, p38, and ERK1/2) and IkBα. Treatment with LRRK2 inhibitor 68 reduced LPS-induced TRAF6/LRRK2 interaction and MAPK and IkBα phosphorylation, thereby reducing TNF-α secretion. These results indicate that LRRK2 is actively involved in proinflammatory responses in human lymphoblasts, and inhibition of GTP binding by 68 results in an anti-inflammation effect against proinflammatory stimuli. These findings not only provide novel insights into the mechanisms of LRRK2-linked immune and inflammatory responses in B-cell-like lymphoblasts, but also suggest that 68 may also have potential therapeutic value for LRRK2-linked immunological disorders. Full article
(This article belongs to the Special Issue LRRK2-Dependent Neurodegeneration in Parkinson’s Disease)
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Article
LRRK2 Modulates the Exocyst Complex Assembly by Interacting with Sec8
Cells 2021, 10(2), 203; https://doi.org/10.3390/cells10020203 - 20 Jan 2021
Viewed by 868
Abstract
Mutations in LRRK2 play a critical role in both familial and sporadic Parkinson’s disease (PD). Up to date, the role of LRRK2 in PD onset and progression remains largely unknown. However, experimental evidence highlights a critical role of LRRK2 in the control of [...] Read more.
Mutations in LRRK2 play a critical role in both familial and sporadic Parkinson’s disease (PD). Up to date, the role of LRRK2 in PD onset and progression remains largely unknown. However, experimental evidence highlights a critical role of LRRK2 in the control of vesicle trafficking, likely by Rab phosphorylation, that in turn may regulate different aspects of neuronal physiology. Here we show that LRRK2 interacts with Sec8, one of eight subunits of the exocyst complex. The exocyst complex is an evolutionarily conserved multisubunit protein complex mainly involved in tethering secretory vesicles to the plasma membrane and implicated in the regulation of multiple biological processes modulated by vesicle trafficking. Interestingly, Rabs and exocyst complex belong to the same protein network. Our experimental evidence indicates that LRRK2 kinase activity or the presence of the LRRK2 kinase domain regulate the assembly of exocyst subunits and that the over-expression of Sec8 significantly rescues the LRRK2 G2019S mutant pathological effect. Our findings strongly suggest an interesting molecular mechanism by which LRRK2 could modulate vesicle trafficking and may have important implications to decode the complex role that LRRK2 plays in neuronal physiology. Full article
(This article belongs to the Special Issue LRRK2-Dependent Neurodegeneration in Parkinson’s Disease)
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Article
Divergent Effects of G2019S and R1441C LRRK2 Mutations on LRRK2 and Rab10 Phosphorylations in Mouse Tissues
Cells 2020, 9(11), 2344; https://doi.org/10.3390/cells9112344 - 22 Oct 2020
Cited by 2 | Viewed by 1084
Abstract
Mutations in LRRK2 cause familial Parkinson’s disease and common variants increase disease risk. LRRK2 kinase activity and cellular localization are tightly regulated by phosphorylation of key residues, primarily Ser1292 and Ser935, which impacts downstream phosphorylation of its substrates, among which Rab10. A comprehensive [...] Read more.
Mutations in LRRK2 cause familial Parkinson’s disease and common variants increase disease risk. LRRK2 kinase activity and cellular localization are tightly regulated by phosphorylation of key residues, primarily Ser1292 and Ser935, which impacts downstream phosphorylation of its substrates, among which Rab10. A comprehensive characterization of LRRK2 activity and phosphorylation in brain as a function of age and mutations is missing. Here, we monitored Ser935 and Ser1292 phosphorylation in midbrain, striatum, and cortex of 1, 6, and 12 months-old mice carrying G2019S and R1441C mutations or murine bacterial artificial chromosome (BAC)-Lrrk2-G2019S. We observed that G2019S and, at a greater extent, R1441C brains display decreased phospho-Ser935, while Ser1292 autophosphorylation increased in G2019S but not in R1441C brain, lung, and kidney compared to wild-type. Further, Rab10 phosphorylation, is elevated in R1441C carrying mice, indicating that the effect of LRRK2 mutations on substrate phosphorylation is not generalizable. In BAC-Lrrk2-G2019S striatum and midbrain, Rab10 phosphorylation, but not Ser1292 autophosphorylation, decreases at 12-months, pointing to autophosphorylation and substrate phosphorylation as uncoupled events. Taken together, our study provides novel evidence that LRRK2 phosphorylation in mouse brain is differentially impacted by mutations, brain area, and age, with important implications as diagnostic markers of disease progression and stratification. Full article
(This article belongs to the Special Issue LRRK2-Dependent Neurodegeneration in Parkinson’s Disease)
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Article
Distinct Roles for RAB10 and RAB29 in Pathogenic LRRK2-Mediated Endolysosomal Trafficking Alterations
Cells 2020, 9(7), 1719; https://doi.org/10.3390/cells9071719 - 17 Jul 2020
Cited by 5 | Viewed by 1200
Abstract
Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) cause familial Parkinson’s disease, and sequence variations are associated with the sporadic form of the disease. LRRK2 phosphorylates a subset of RAB proteins implicated in secretory and recycling trafficking pathways, including RAB8A and [...] Read more.
Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) cause familial Parkinson’s disease, and sequence variations are associated with the sporadic form of the disease. LRRK2 phosphorylates a subset of RAB proteins implicated in secretory and recycling trafficking pathways, including RAB8A and RAB10. Another RAB protein, RAB29, has been reported to recruit LRRK2 to the Golgi, where it stimulates its kinase activity. Our previous studies revealed that G2019S LRRK2 expression or knockdown of RAB8A deregulate epidermal growth factor receptor (EGFR) trafficking, with a concomitant accumulation of the receptor in a RAB4-positive recycling compartment. Here, we show that the G2019S LRRK2-mediated EGFR deficits are mimicked by knockdown of RAB10 and rescued by expression of active RAB10. By contrast, RAB29 knockdown is without effect, but expression of RAB29 also rescues the pathogenic LRRK2-mediated trafficking deficits independently of Golgi integrity. Our data suggest that G2019S LRRK2 deregulates endolysosomal trafficking by impairing the function of RAB8A and RAB10, while RAB29 positively modulates non-Golgi-related trafficking events impaired by pathogenic LRRK2. Full article
(This article belongs to the Special Issue LRRK2-Dependent Neurodegeneration in Parkinson’s Disease)
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Review

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Review
Mind the Gap: LRRK2 Phenotypes in the Clinic vs. in Patient Cells
Cells 2021, 10(5), 981; https://doi.org/10.3390/cells10050981 - 22 Apr 2021
Viewed by 867
Abstract
Mutations in the Parkinson’s disease (PD) protein Leucine Rich Repeat Kinase 2 (LRRK2) have been under study for more than 15 years and our understanding of the cellular phenotypes for the pathogenic mutant forms of LRRK2 has significantly advanced. In parallel to research [...] Read more.
Mutations in the Parkinson’s disease (PD) protein Leucine Rich Repeat Kinase 2 (LRRK2) have been under study for more than 15 years and our understanding of the cellular phenotypes for the pathogenic mutant forms of LRRK2 has significantly advanced. In parallel to research on LRRK2 mutations in experimental systems, clinical characterization of patients carrying LRRK2 mutations has advanced, as has the analysis of cells that are derived from these patients, including fibroblasts, blood-derived cells, or cells rendered pluripotent. Under the hypothesis that patient clinical phenotypes are a consequence of a cascade of underlying molecular mechanisms gone astray, we currently have a unique opportunity to compare findings from patients and patient-derived cells to ask the question of whether the clinical phenotype of LRRK2 Parkinson’s disease and cellular phenotypes of LRRK2 patient-derived cells may be mutually informative. In this review, we aim to summarize the available information on phenotypes of LRRK2 mutations in the clinic, in patient-derived cells, and in experimental models in order to better understand the relationship between the three at the molecular and cellular levels and identify trends and gaps in correlating the data. Full article
(This article belongs to the Special Issue LRRK2-Dependent Neurodegeneration in Parkinson’s Disease)
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Review
Pathological Functions of LRRK2 in Parkinson’s Disease
Cells 2020, 9(12), 2565; https://doi.org/10.3390/cells9122565 - 30 Nov 2020
Cited by 6 | Viewed by 1012
Abstract
Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are common genetic risk factors for both familial and sporadic Parkinson’s disease (PD). Pathogenic mutations in LRRK2 have been shown to induce changes in its activity, and abnormal increase in LRRK2 kinase activity [...] Read more.
Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are common genetic risk factors for both familial and sporadic Parkinson’s disease (PD). Pathogenic mutations in LRRK2 have been shown to induce changes in its activity, and abnormal increase in LRRK2 kinase activity is thought to contribute to PD pathology. The precise molecular mechanisms underlying LRRK2-associated PD pathology are far from clear, however the identification of LRRK2 substrates and the elucidation of cellular pathways involved suggest a role of LRRK2 in microtubule dynamics, vesicular trafficking, and synaptic transmission. Moreover, LRRK2 is associated with pathologies of α-synuclein, a major component of Lewy bodies (LBs). Evidence from various cellular and animal models supports a role of LRRK2 in the regulation of aggregation and propagation of α-synuclein. Here, we summarize our current understanding of how pathogenic mutations dysregulate LRRK2 and discuss the possible mechanisms leading to neurodegeneration. Full article
(This article belongs to the Special Issue LRRK2-Dependent Neurodegeneration in Parkinson’s Disease)
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Review
Alpha-Synuclein and LRRK2 in Synaptic Autophagy: Linking Early Dysfunction to Late-Stage Pathology in Parkinson’s Disease
Cells 2020, 9(5), 1115; https://doi.org/10.3390/cells9051115 - 30 Apr 2020
Cited by 4 | Viewed by 1545
Abstract
The lack of effective disease-modifying strategies is the major unmet clinical need in Parkinson’s disease. Several experimental approaches have attempted to validate cellular targets and processes. Of these, autophagy has received considerable attention in the last 20 years due to its involvement in [...] Read more.
The lack of effective disease-modifying strategies is the major unmet clinical need in Parkinson’s disease. Several experimental approaches have attempted to validate cellular targets and processes. Of these, autophagy has received considerable attention in the last 20 years due to its involvement in the clearance of pathologic protein aggregates and maintenance of neuronal homeostasis. However, this strategy mainly addresses a very late stage of the disease, when neuropathology and neurodegeneration have likely “tipped over the edge” and disease modification is extremely difficult. Very recently, autophagy has been demonstrated to modulate synaptic activity, a process distinct from its catabolic function. Abnormalities in synaptic transmission are an early event in neurodegeneration with Leucine-Rich Repeat Kinase 2 (LRRK2) and alpha-synuclein strongly implicated. In this review, we analyzed these processes separately and then discussed the unification of these biomolecular fields with the aim of reconstructing a potential “molecular timeline” of disease onset and progression. We postulate that the elucidation of these pathogenic mechanisms will form a critical basis for the design of novel, effective disease-modifying therapies that could be applied early in the disease process. Full article
(This article belongs to the Special Issue LRRK2-Dependent Neurodegeneration in Parkinson’s Disease)
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Other

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Perspective
The Michael J. Fox Foundation’s Strategies for Accelerating Translation of LRRK2 into Therapies for Parkinson Disease
Cells 2020, 9(8), 1878; https://doi.org/10.3390/cells9081878 - 11 Aug 2020
Cited by 2 | Viewed by 1275
Abstract
Since 2005, The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has invested significant funding and non-funding effort to accelerate research and drug development activity around the Parkinson disease (PD)-associated protein LRRK2. MJFF has spearheaded multiple public/private pre-competitive collaborations that have contributed to [...] Read more.
Since 2005, The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has invested significant funding and non-funding effort to accelerate research and drug development activity around the Parkinson disease (PD)-associated protein LRRK2. MJFF has spearheaded multiple public/private pre-competitive collaborations that have contributed to our understanding of LRRK2 function; de-risked potential safety questions around the therapeutic use of LRRK2 kinase inhibitors; and generated critical research tools, biosamples, and data for the field. Several LRRK2-targeted therapies are now in human testing due to the hard work of so many in the PD community. In this perspective, we present a holistic description and model of how our Foundation’s support targeted important barriers to LRRK2 research and helped move the field into clinical trials. Full article
(This article belongs to the Special Issue LRRK2-Dependent Neurodegeneration in Parkinson’s Disease)
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