LRRK2 inhibition prevents endolysosomal deficits seen in human Parkinson's disease

Rocha, Emily M.; Miranda, Briana R. De; Castro, Sandra L.; Drolet, Robert E.; Hatcher, Nathan G.; Yao, Lihang; Smith, Sean M.; Keeney, Matthew T.; Maio, Roberto Di; Kofler, Julia; Hastings, Teresa G.; Greenamyre, J. Timothy

doi:10.1016/j.nbd.2019.104626

Cited by 78 publications

(105 citation statements)

References 37 publications

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“…Although, the authors did not investigate whether this effect was due to a reduced α-syn burden mediated by an increase of the proteolytic events, this study revealed that pharmacological LRRK2 kinase inhibition could represent an appealing therapeutic approach also to idiopathic PD. This was confirmed by Greenamyre and collaborators who reported that repeated rotenone administration caused pSer1292 LRRK2 phosphorylation (index of LRRK2 activation) and pSer129 α-syn accumulation (possible early index of neurotoxicity) in SNc neurons, along with loss of nigrostriatal DA neurons which were reversed by systemic administration of the thirdgeneration (West, 2017) LRRK2 inhibitor PF-360 (Di Maio et al, 2018;Rocha et al, 2019). Conversely, Henderson et al (2019) failed to observe neuroprotection and clearance of α-syn aggregates in naïve mice injected with α-syn preformed fibrils (PFF), and chronically administered with the potent thirdgeneration LRRK2 kinase inhibitor MLi-2.…”

Section: Are Alp Changes Observed In Lrrk2 Models Relevant For Lrrk2-mentioning

confidence: 63%

Autophagy and LRRK2 in the Aging Brain

2019

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Autophagy is a highly conserved process by which long-lived macromolecules, protein aggregates and dysfunctional/damaged organelles are delivered to lysosomes for degradation. Autophagy plays a crucial role in regulating protein quality control and cell homeostasis in response to energetic needs and environmental challenges. Indeed, activation of autophagy increases the lifespan of living organisms, and impairment of autophagy is associated with several human disorders, among which neurodegenerative disorders of aging, such as Parkinson's disease. These disorders are characterized by the accumulation of aggregates of aberrant or misfolded proteins that are toxic for neurons. Since aging is associated with impaired autophagy, autophagy inducers have been viewed as a strategy to counteract the age-related physiological decline in brain functions and emergence of neurodegenerative disorders. Parkinson's disease is a hypokinetic, multisystemic disorder characterized by agerelated, progressive degeneration of central and peripheral neuronal populations, associated with intraneuronal accumulation of proteinaceous aggregates mainly composed by the presynaptic protein α-synuclein. α-synuclein is a substrate of macroautophagy and chaperone-mediated autophagy (two major forms of autophagy), thus impairment of its clearance might favor the process of α-synuclein seeding and spreading that trigger and sustain the progression of this disorder. Genetic factors causing Parkinson's disease have been identified, among which mutations in the LRRK2 gene, which encodes for a multidomain protein encompassing central GTPase and kinase domains, surrounded by protein-protein interaction domains. Six LRRK2 mutations have been pathogenically linked to Parkinson's disease, the most frequent being the G2019S in the kinase domain. LRRK2-associated Parkinson's disease is clinically and neuropathologically similar to idiopathic Parkinson's disease, also showing age-dependency and incomplete penetrance. Several mechanisms have been proposed through which LRRK2 mutations can lead to Parkinson's disease. The present article will focus on the evidence that LRRK2 and its mutants are associated with autophagy dysregulation. Studies in cell lines and neurons in vitro and in LRRK2 knockout , knock-in, kinase-dead and transgenic animals in vivo will be reviewed. The role of aging in LRRK2-induced synucleinopathy will be discussed. Possible mechanisms underlying the LRRK2-mediated control over autophagy will be analyzed, and the contribution of autophagy dysregulation to the neurotoxic actions of LRRK2 will be examined.

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Section: Are Alp Changes Observed In Lrrk2 Models Relevant For Lrrk2-mentioning

confidence: 63%

Autophagy and LRRK2 in the Aging Brain

2019

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“…However, few studies have linked inflammation and immunity to the function of RIPK4-RIPK7 (19). Some studies have also shown that RIPK6 and RIPK7 play important roles in Parkinson's disease (23)(24)(25). Current results demonstrate that the members of each family of RIPKs are ubiquitous and highly conserved in vertebrates.…”

Section: Introductionmentioning

confidence: 75%

Comprehensive Evolutionary Analysis of Lamprey TNFR-Associated Factors (TRAFs) and Receptor-Interacting Protein Kinase (RIPKs) and Insights Into the Functional Characterization of TRAF3/6 and RIPK1

Hou

Pang

2020

Front. Immunol.

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TNFR-associated factors (TRAFs) and receptor-interacting protein kinases (RIPKs) are important immunological linker molecules in mammals and play important roles in the TNFα, TLR and IFN signaling pathways. However, the evolutionary origins of these genes in vertebrates have not previously been described in lampreys. In this study, we searched the genomes of Lampetra japonicum, Lethenteron reissneri, and Petromyzon marinus for genes encoding trafs and ripks and performed homologous sequence alignment, phylogenetic tree, functional domain, conserved motif, gene structure, and synteny analyses to determine their evolutionary relationships. The distribution of the lamprey traf and ripk families and the immune response of the gene families in lampreys stimulated by different pathogens were also demonstrated, suggesting a role of structural changes in expression and functional diversification. Additionally, the dual luciferase reporter gene assay showed that the addition of exogenous immunomodulator (TNFα or IFN) to the overexpression of LjLRIPK1a or LjTRAF3/6 significantly downregulated NF-κB or ISRE activation. LjRIPK1a can significantly enhance caspase-8 activity, and overexpression of LjRIPK1a or LjTRAF3a/6 in HEK293T cells results in cell apoptosis. In summary, this study makes an important contribution to the understanding of the traf and ripk gene families in different vertebrates. Our results also provide new evidence for the evolution of vertebrate TRAFs and RIPKs and their impacts on immune regulation.

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“…Recent studies suggest increased LRRK2 kinase activity and endolysosomal pathology in nigral dopaminergic neurons from brains of sporadic PD subjects, including the accumulation of Rab5-positive early endosomes, depletion of late endosomes, depletion of lysosomes, and depletion of lysosomal GCase [67,68]. Whether these vesicular abnormalities are dependent on LRRK2 activity is uncertain.…”

Section: Lrrk2mentioning

confidence: 99%

LRRK2 and the Endolysosomal System in Parkinson’s Disease

Erb

Moore

2020

JPD

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Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant familial Parkinson’s disease (PD), with pathogenic mutations enhancing LRRK2 kinase activity. There is a growing body of evidence indicating that LRRK2 contributes to neuronal damage and pathology both in familial and sporadic PD, making it of particular interest for understanding the molecular pathways that underlie PD. Although LRRK2 has been extensively studied to date, our understanding of the seemingly diverse functions of LRRK2 throughout the cell remains incomplete. In this review, we discuss the functions of LRRK2 within the endolysosomal pathway. Endocytosis, vesicle trafficking pathways, and lysosomal degradation are commonly disrupted in many neurodegenerative diseases, including PD. Additionally, many PD-linked gene products function in these intersecting pathways, suggesting an important role for the endolysosomal system in maintaining protein homeostasis and neuronal health in PD. LRRK2 activity can regulate synaptic vesicle endocytosis, lysosomal function, Golgi network maintenance and sorting, vesicular trafficking and autophagy, with alterations in LRRK2 kinase activity serving to disrupt or regulate these pathways depending on the distinct cell type or model system. LRRK2 is critically regulated by at least two proteins in the endolysosomal pathway, Rab29 and VPS35, which may serve as master regulators of LRRK2 kinase activity. Investigating the function and regulation of LRRK2 in the endolysosomal pathway in diverse PD models, especially in vivo models, will provide critical insight into the cellular and molecular pathophysiological mechanisms driving PD and whether LRRK2 represents a viable drug target for disease-modification in familial and sporadic PD.

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LRRK2 inhibition prevents endolysosomal deficits seen in human Parkinson's disease

Cited by 78 publications

References 37 publications

Autophagy and LRRK2 in the Aging Brain

Autophagy and LRRK2 in the Aging Brain

Comprehensive Evolutionary Analysis of Lamprey TNFR-Associated Factors (TRAFs) and Receptor-Interacting Protein Kinase (RIPKs) and Insights Into the Functional Characterization of TRAF3/6 and RIPK1

LRRK2 and the Endolysosomal System in Parkinson’s Disease

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