LRRK2 and idiopathic Parkinson’s disease

Rocha, Emily M.; Keeney, Matthew T.; Maio, Roberto Di; Miranda, Briana R. De; Greenamyre, J. Timothy

doi:10.1016/j.tins.2021.12.002

Cited by 65 publications

(63 citation statements)

References 108 publications

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“…Given our findings that (i) LRRK2 is activated in nigral neurons in iPD ( Di Maio et al, 2018 ), NOX2 activity is required for wildtype LRRK2 activation in vivo , and (iii) NOX2 is activated in nigral neurons in iPD, it appears likely this mechanism is operative in the human disease. Endolysosomal deficits and autophagic dysfunction contribute to the progression of PD ( Rocha et al, 2020 ; Rocha et al, 2022 ). Interestingly, aberrant LRRK2 kinase activity has been shown to lead to autophagic dysfunction and endolysosomal deficits with the consequence of accumulation of α-synuclein ( Di Maio et al, 2018 ; Rocha et al, 2020 ; Rocha et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…Endolysosomal deficits and autophagic dysfunction contribute to the progression of PD ( Rocha et al, 2020 ; Rocha et al, 2022 ). Interestingly, aberrant LRRK2 kinase activity has been shown to lead to autophagic dysfunction and endolysosomal deficits with the consequence of accumulation of α-synuclein ( Di Maio et al, 2018 ; Rocha et al, 2020 ; Rocha et al, 2022 ). Treatment with a LRRK2 kinase inhibitor prevented these deficits in the rotenone rat model (50), suggesting that elevated kinase activity contributes to this process ( Graphical Abstract ).…”

Section: Discussionmentioning

confidence: 99%

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NADPH oxidase 2 activity in Parkinson's disease

Keeney

Hoffman

Farmer

et al. 2022

Neurobiology of Disease

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

NADPH oxidase 2 activity in Parkinson's disease

Keeney

Hoffman

Farmer

et al. 2022

Neurobiology of Disease

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“…The functions of LRRK2 are not fully understood, but it has become clear that LRRK2 can trigger autophosphorylation at Ser1292 and phosphorylate a subset of Rab small GTPases (Rab8A and Rab10) (Rocha et al, 2022; Sheng et al, 2012; Steger et al, 2016). A direct readout of these targets was not present in our panel of stains.…”

Section: Discussionmentioning

confidence: 99%

Machine learning-aided multidimensional phenotyping of Parkinson’s disease patient stem cell-derived midbrain dopaminergic neurons

Vuidel¹,

Cousin²,

Weykopf

et al. 2022

Preprint

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Combining multiple Parkinson's disease (PD) relevant cellular phenotypes might increase the accuracy of midbrain dopaminergic (mDA) in vitro models. We differentiated patient-derived induced pluripotent stem cells (iPSCs) with a LRRK2 G2019S mutation, isogenic control and genetically unrelated iPSCs into mDA neurons. Using automated fluorescence microscopy in 384-well plate format, we identified elevated levels of α-synuclein and Serine 129 phosphorylation (pS129), reduced dendritic complexity, and mitochondrial dysfunction. Next, we measured additional image-based phenotypes and used machine learning (ML) to accurately classify mDA neurons according to their genotype. Additionally, we show that chemical compound treatments, targeting LRRK2 kinase activity or α-synuclein levels, are detectable when using ML classification based on multiple image-based phenotypes. We validated our approach using a second isogenic patient derived SNCA gene triplication mDA neuronal model. This phenotyping and classification strategy improves the exploitability of mDA neurons for disease modelling and the identification of novel PD drug targets.

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“…Currently, delivering LRRK2 kinase inhibitors such as DNL151 has become an important avenue for treating LRRK2 diseased patients ( Ding and Ren, 2020 ). Mutations in LRRK2 are a relatively common cause of familial late-onset PD, and also linked to the more numerous sporadic PD, suggesting that understanding LRRK2-associated mechanisms might be a gateway to exploring sporadic PD ( Rocha et al, 2022 ). Notably, the multi-domain structure of LRRK2 renders its versatile functions in multiple physiological processes, including migration, autophagy, phagocytosis, and mitochondrial function, among others.…”

Section: Introductionmentioning

confidence: 99%

The Double-Faceted Role of Leucine-Rich Repeat Kinase 2 in the Immunopathogenesis of Parkinson’s Disease

Zhang

Ren

et al. 2022

Front. Aging Neurosci.

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Leucine-rich repeat kinase 2 (LRRK2) is one of the most common causative genes in Parkinson’s disease (PD). The complex structure of this multiple domains’ protein determines its versatile functions in multiple physiological processes, including migration, autophagy, phagocytosis, and mitochondrial function, among others. Mounting studies have also demonstrated the role of LRRK2 in mediating neuroinflammation, the prominent hallmark of PD, and intricate functions in immune cells, such as microglia, macrophages, and astrocytes. Of those, microglia were extensively studied in PD, which serves as the resident immune cell of the central nervous system that is rapidly activated upon neuronal injury and pathogenic insult. Moreover, the activation and function of immune cells can be achieved by modulating their intracellular metabolic profiles, in which LRRK2 plays an emerging role. Here, we provide an updated review focusing on the double-faceted role of LRRK2 in regulating various cellular physiology and immune functions especially in microglia. Moreover, we will summarize the latest discovery of the three-dimensional structure of LRRK2, as well as the function and dysfunction of LRRK2 in immune cell-related pathways.

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LRRK2 and idiopathic Parkinson’s disease

Cited by 65 publications

References 108 publications

NADPH oxidase 2 activity in Parkinson's disease

NADPH oxidase 2 activity in Parkinson's disease

Machine learning-aided multidimensional phenotyping of Parkinson’s disease patient stem cell-derived midbrain dopaminergic neurons

The Double-Faceted Role of Leucine-Rich Repeat Kinase 2 in the Immunopathogenesis of Parkinson’s Disease

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