Physiology versus pathology in Parkinson's disease

Nakamura, Ken; Edwards, Robert H.

doi:10.1073/pnas.0704254104

Cited by 10 publications

(3 citation statements)

References 26 publications

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“…Therefore, one could speculate that LRRK2, a-synuclein and Parkin function in a common pathway at the synapse and disturbances of this pathway have a role in Parkinson's disease. Interestingly, defects in synaptic transmission are frequently and consistently observed in both dominant and recessive forms of Parkinson's disease (Kitada et al, 2009;Nakamura and Edwards, 2007;Tong et al, 2009), although the molecular mechanisms remain unknown. Further studies are now needed to determine whether this intriguing common synaptic function of LRRK2 and other Parkinson's disease risk factors contributes to Parkinson's disease pathology associated with these genes.…”

Section: Discussionmentioning

confidence: 99%

LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism

Arranz

Delbroek

Kolen

et al. 2014

Journal of Cell Science

140

136

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Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease, but the precise physiological function of the protein remains ill-defined. Recently, our group proposed a model in which LRRK2 kinase activity is part of an EndoA phosphorylation cycle that facilitates efficient vesicle formation at synapses in the Drosophila melanogaster neuromuscular junctions. Flies harbor only one Lrrk gene, which might encompass the functions of both mammalian LRRK1 and LRRK2. We therefore studied the role of LRRK2 in mammalian synaptic function and provide evidence that knockout or pharmacological inhibition of LRRK2 results in defects in synaptic vesicle endocytosis, altered synaptic morphology and impairments in neurotransmission. In addition, our data indicate that mammalian endophilin A1 (EndoA1, also known as SH3GL2) is phosphorylated by LRRK2 in vitro at T73 and S75, two residues in the BAR domain. Hence, our results indicate that LRRK2 kinase activity has an important role in the regulation of clathrin-mediated endocytosis of synaptic vesicles and subsequent neurotransmission at the synapse.

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Section: Discussionmentioning

confidence: 99%

LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism

Arranz

Delbroek

Kolen

et al. 2014

Journal of Cell Science

140

136

View full text Add to dashboard Cite

show abstract

“…How could this be relevant to PD? One of the most consistent and intriguing findings associated with both dominant (Tong et al, 2009) and recessive (Nakamura and Edwards, 2007) forms of PD, including those due to parkin mutations (Kitada et al, 2009), has been defects in synaptic transmission, possibly related to altered synaptic vesicle endocytosis, recycling, or release. Yet the molecular mechanisms involved have remained completely unknown.…”

Section: Implication Of Parkin-mediated Ubiquitination In Synaptic Transmission and Pdmentioning

confidence: 99%

SH3 Domains from a Subset of BAR Proteins Define a Ubl-Binding Domain and Implicate Parkin in Synaptic Ubiquitination

et al. 2009

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Mutations in the parkin gene are responsible for a common inherited form of Parkinson's disease (PD). Parkin is a RING-type E3 ubiquitin ligase with an N-terminal ubiquitin-like domain (Ubl). We report here that the parkin Ubl binds SH3 domains from endocytic BAR proteins such as endophilin-A with an affinity comparable to proline-rich domains (PRDs) from well-established SH3 partners. The NMR structure of the Ubl-SH3 complex identifies the PaRK extension, a unique C-terminal motif in the parkin Ubl required for SH3 binding and for parkin-mediated ubiquitination of endophilin-A in vitro. In nerve terminals, conditions that promote phosphorylation enhance the interaction between parkin and endophilin-A and increase the levels of ubiquitinated proteins within PRD-associated synaptic protein complexes in wild-type but not parkin knockout brain. The findings identify a pathway for the recruitment of synaptic substrates to parkin with the potential to explain the defects in synaptic transmission observed in recessive forms of PD.

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“…Loss of function of PINK1 is closely associated with early-onset of Parkinson’s disease (PD)(Reed et al, 2019,Pickrell et al, 2015), a neurodegenerative disease characterized by the dysfunction of dopaminergic (DA) neurons in the substantia nigra (SN)(Goldstein et al, 2019,Poewe et al, 2017). The pathology of PD caused by PINK1 mutationsis unclear, largely due to that the PINK1 knock-out mouse and pig models were unable to recapitulate the typical PD-associated symptoms observed in human patients(Nakamura et al, 2007,Dawson et al, 2010,Zhou et al, 2015). Thus, it is necessary to generate a PINK1 mutant animal model in non-human primates (NHPs),which show high similarity to human, to uncover the unique function of PINK1 in primate brains.…”

Section: Introductionmentioning

confidence: 99%

MutatingPINK1gene by paired truncated sgRNA/Cas9-D10A in Cynomolgus Monkey

Chen

Kang

Yang

et al. 2020

Preprint

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Mutations of PINK1 cause early-onset Parkinson's disease (PD) with selective neurodegeneration in humans. However, current PINK1 knockout mouse and pig models are unable to recapitulate the typical neurodegenerative phenotypes observed in PD patients, indicating that it is essential to generate PINK1 disease models in non-human primates (NHPs) that are highly close to humans, to investigate the unique function of PINK1 in primate brains. Paired single guide RNA (sgRNA)/Cas9-D10A nickases and truncated sgRNA/Cas9, both enabling the reduction of the off-target effect without apparently compromising the on-target editing, are two optimized strategies in applying the CRISPR/Cas9 system to establish disease animal models. Here, we combined the two strategies and injected Cas9-D10A mRNA and two truncated sgRNAs into one-cell-stage cynomolgus zygotes to target PINK1 gene. We show precise and efficient gene editing of the target site in the three new born cynomolgus monkeys. The frame shift mutations of PINK1 in mutant fibroblasts leaded to the reduction of the mRNA, However, western-blot and immunofluorescence staining confirmed the PINK1 protein levels were comparable to that in the wild-type fibroblasts. We further reprogramed mutant fibroblast into induced pluripotent stem cells (iPSCs) and they show similar ability of differentiation into dopamine (DA) neurons. Taken together, our results showed that coinjection of Cas9-D10A nickase mRNA and sgRNA into one-cell-stage cynomolgus embryos enable the generation of human disease models in NHPs and the target editing by paired truncated sgRNA/Cas9-D10A in PINK1 gene exon 2 did not impact the protein expression.

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Physiology versus pathology in Parkinson's disease

Cited by 10 publications

References 26 publications

LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism

LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism

SH3 Domains from a Subset of BAR Proteins Define a Ubl-Binding Domain and Implicate Parkin in Synaptic Ubiquitination

MutatingPINK1gene by paired truncated sgRNA/Cas9-D10A in Cynomolgus Monkey

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