LRRK2 Biology from structure to dysfunction: research progresses, but the themes remain the same

Berwick, Daniel C.; Heaton, George R.; Azeggagh, Sonia; Harvey, Kirsten

doi:10.1186/s13024-019-0344-2

Cited by 133 publications

(154 citation statements)

References 216 publications

(307 reference statements)

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“…Since the abnormal enhancement of LRRK2 kinase activity is implicated in the PD-related LRRK2 mutants, including the most common G2019S mutation, extensive efforts have been devoted to the development of LRRK2 kinase inhibitors as potential therapeutic agents [10]. However, increasing evidence also highlights the functional significance of LRRK2 in various cellular processes in the brain and peripheral organs.…”

Section: Discussionmentioning

confidence: 99%

“…8a, b). The PD-related G2019S missense mutation in LRRK2 kinase domain is generally regarded to cause an increase of LRRK2 kinase activity [10]. We next cultured SPNs from Lrrk2 G2019S homozygous KI (GS/GS) mice for 3 weeks and found that G2019S mutation caused a similarly substantial increase in nuclear size, with only a modest reduction in nuclear invaginations compared to controls (Fig.…”

Section: Lrrk2 −/− Mice Develop Age-dependent Motor Abnormalitiesmentioning

confidence: 93%

“…The malfunction of LRRK2 kinase and GTPase domains induces differential nuclear morphological alterations LRRK2 protein possesses multiple functional and structural domains, including a protein kinase domain and a small GTPase domain [10]. To investigate whether LRRK2 kinase activity regulates nuclear morphology, we treated cultured Lrrk2 +/+ SPNs for 24 h with 3 nM MLi-2, a potent and selective LRRK2 kinase inhibitor [43].…”

Section: Lrrk2 −/− Mice Develop Age-dependent Motor Abnormalitiesmentioning

confidence: 99%

“…LRRK2 gene locus has also been associated with sporadic PD [3,4]. Extensive studies have been focusing on understanding the pathogenic mechanisms of PDrelated LRRK2 mutations [5][6][7][8][9][10]. Notably, the genetic burden of LRRK2 variants appears to correlate with the age at onset of disease [11] and the penetrance of LRRK2 mutations is increased with age [4].…”

Section: Introductionmentioning

confidence: 99%

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Parkinson’s disease-related Leucine-rich repeat kinase 2 modulates nuclear morphology and genomic stability in striatal projection neurons during aging

Chen

Xie

Tian

et al. 2020

Mol Neurodegeneration

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Background: Multiple missense mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with familial forms of late onset Parkinson's disease (PD), the most common age-related movement disorder. The dysfunction of dopamine transmission contributes to PD-related motor symptoms. Interestingly, LRRK2 is more abundant in the dopaminoceptive striatal spiny projection neurons (SPNs) compared to the dopamine-producing nigrostriatal dopaminergic neurons. Aging is the most important risk factor for PD and other neurodegenerative diseases. However, whether LRRK2 modulates the aging of SPNs remains to be determined. Methods: We conducted RNA-sequencing (RNA-seq) analyses of striatal tissues isolated from Lrrk2 knockout (Lrrk2 −/−) and control (Lrrk2 +/+) mice at 2 and 12 months of age. We examined SPN nuclear DNA damage and epigenetic modifications; SPN nuclear, cell body and dendritic morphology; and the locomotion and motor skill learning of Lrrk2 +/+ and Lrrk2 −/− mice from 2 to 24 months of age. Considering the strength of cell cultures for future mechanistic studies, we also performed preliminary studies in primary cultured SPNs derived from the Lrrk2 +/+ and Lrrk2 −/− mice as well as the PD-related Lrrk2 G2019S and R1441C mutant mice. Results: Lrrk2-deficiency accelerated nuclear hypertrophy and induced dendritic atrophy, soma hypertrophy and nuclear invagination in SPNs during aging. Additionally, increased nuclear DNA damage and abnormal histone methylations were also observed in aged Lrrk2 −/− striatal neurons, together with alterations of molecular pathways involved in regulating neuronal excitability, genome stability and protein homeostasis. Furthermore, both the PDrelated Lrrk2 G2019S mutant and LRRK2 kinase inhibitors caused nuclear hypertrophy, while the Lrrk2 R1441C mutant and γ-Aminobutyric acid type A receptor (GABA-AR) inhibitors promoted nuclear invagination in the cultured SPNs. On the other hand, inhibition of neuron excitability prevented the formation of nuclear invagination in the cultured Lrrk2 −/− and R1441C SPNs. Conclusions: Our findings support an important physiological function of LRRK2 in maintaining nuclear structure integrity and genomic stability during the normal aging process, suggesting that PD-related LRRK2 mutations may cause the deterioration of neuronal structures through accelerating the aging process.

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Section: Discussionmentioning

confidence: 99%

Section: Lrrk2 −/− Mice Develop Age-dependent Motor Abnormalitiesmentioning

confidence: 93%

Section: Lrrk2 −/− Mice Develop Age-dependent Motor Abnormalitiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Parkinson’s disease-related Leucine-rich repeat kinase 2 modulates nuclear morphology and genomic stability in striatal projection neurons during aging

Chen

Xie

Tian

et al. 2020

Mol Neurodegeneration

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“…Lrrk2 encodes a ~280 kDa protein that contains multiple enzymatic domains and protein–protein interacting domains (Figure 1). These include armadillo‐like repeats (ARM), ankyrin repeats (ANK), leucine‐rich repeats (LRR), and a WD40 domain, which all function as sites for protein–protein interactions (Berwick, Heaton, Azeggagh, & Harvey, 2019). The enzymatic domains of Lrrk2 include the kinase domain and the GTPase domain, which is comprised of the Roc (Ras of complex protein) and COR (C‐terminal of Roc) domains (Langston, Rudenko, & Cookson, 2016).…”

Section: Introductionmentioning

confidence: 99%

Lrrk2 modulation of Wnt signaling during zebrafish development

Wint

Sirotkin

2020

J of Neuroscience Research

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Mutations in leucine‐rich repeat kinase 2 (lrrk2) are the most common genetic cause of Parkinson's disease. Difficulty in elucidating the pathogenic mechanisms resulting from disease‐associated Lrrk2 variants stems from the complexity of Lrrk2 function and activities. Lrrk2 contains multiple protein–protein interacting domains, a GTPase domain, and a kinase domain. Lrrk2 is implicated in many cellular processes including vesicular trafficking, autophagy, cytoskeleton dynamics, and Wnt signaling. Here, we generated a zebrafish lrrk2 allelic series to study the requirements for Lrrk2 during development and to dissect the importance of its various domains. The alleles are predicted to encode proteins that either lack all functional domains (lrrk2sbu304), the GTPase, and kinase domains (lrrk2sbu71) or the kinase domain (lrrk2sbu96). All three lrrk2 mutants are viable, morphologically normal, and display wild‐type‐like locomotion. Because Lrrk2 modulates Wnt signaling in some contexts, we assessed Wnt signaling in all three mutant lines. Analysis of Wnt signaling by studying the expression of target genes using whole mount RNA in situ hybridization and a transgenic Wnt reporter revealed wild‐type domains of Wnt activity in each of the mutants. However, we found that Wnt pathway activation is attenuated in lrrk2sbu304/sbu304, which lacks both scaffolding and catalytic domains, but not in the other alleles during late embryogenesis. This supports a model in which Lrrk2 scaffolding functions are key to a context‐dependent role in promoting canonical Wnt signaling.

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Pharmacologic screen identifies active combinations with BET inhibitors and LRRK2 as a novel putative target in lymphoma

Spriano

Sartori

Tarantelli

et al. 2022

eJHaem

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Inhibitors of the Bromo-and Extra-Terminal domain (BET) family proteins have strong preclinical antitumor activity in multiple tumor models, including lymphomas. Limited single-agent activity has been reported in the clinical setting. Here, we have performed a pharmacological screening to identify compounds that can increase the antitumor activity of BET inhibitors in lymphomas.The germinal center B-cell like diffuse large B-cell lymphoma (DLBCL) cell lines OCI-LY-19 and WSU-DLCL2 were exposed to 348 compounds given as single agents at two different concentrations and in combination with the BET inhibitor birabresib.The combination partners included small molecules targeting important biologic pathways such as PI3K/AKT/MAPK signaling and apoptosis, approved anticancer agents, kinase inhibitors, epigenetic compounds. The screening identified a series of compounds leading to a stronger antiproliferative activity when given in combination than as single agents: the histone deacetylase (HDAC) inhibitors panobinostat and dacinostat, the mTOR (mechanistic target of rapamycin) inhibitor everolimus, the ABL/SRC (ABL proto-oncogene/SRC proto oncogene) inhibitor dasatinib, the AKT1/2/3 inhibitor MK-2206, the JAK2 inhibitor TG101209. The novel finding was the benefit given by the addition of the LRRK2 inhibitor LRRK2-IN-1, which was validated in vitro and in vivo.Genetic silencing demonstrated that LRRK2 sustains the proliferation of lymphoma cells, a finding paired with the association between high expression levels and inferior outcome in DLBCL patients.We identified combinations that can improve the response to BET inhibitors in lymphomas, and LRRK2 as a gene essential for lymphomas and as putative novel target for this type of tumors. Filippo Spriano and Giulio Sartori are the co-first authors.

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LRRK2 Biology from structure to dysfunction: research progresses, but the themes remain the same

Cited by 133 publications

References 216 publications

Parkinson’s disease-related Leucine-rich repeat kinase 2 modulates nuclear morphology and genomic stability in striatal projection neurons during aging

Parkinson’s disease-related Leucine-rich repeat kinase 2 modulates nuclear morphology and genomic stability in striatal projection neurons during aging

Lrrk2 modulation of Wnt signaling during zebrafish development

Pharmacologic screen identifies active combinations with BET inhibitors and LRRK2 as a novel putative target in lymphoma

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