LRRK2 regulates synaptic vesicle endocytosis

Shin, Na‐Rae; Jeong, Hyerhan; Kwon, Jungsun; Heo, Hye Young; Kwon, Jung June; Yun, Hye Jin; Kim, Cy Hyun; Han, Baek Soo; Tong, Yiwei; Shen, Jie; Hatano, Taku; Hattori, Nobutaka; Kim, Kwang S.; Chang, Sunghoe; Seol, Wongi

doi:10.1016/j.yexcr.2008.02.015

Cited by 309 publications

(357 citation statements)

References 46 publications

Supporting

Mentioning

340

Contrasting

Order By: Relevance

“…indicates a role of LRRK2 in synaptic vesicle endocytosis because LRRK2 knockout as well as the common G2019S LRRK2 mutant slow down synaptic vesicle endocytosis [74]. Similar observations were made in Drosophila LRRK2 loss-of-function mutants [64], and recently also in neurons from LRRK2 knockout mice [75].…”

Section: [ 4 5 5 _ T D $ D I F F ] A-synuclein -A Possible Role In Slsupporting

confidence: 66%

“…Furthermore, inhibitors of LRRK2 kinase activity seem to reduce synaptic vesicle endocytosis [76]. Different mechanisms have been discussed, and LRRK2 has been found to phosphorylate mammalian endophilin A1 [75] as well as Rab5b [74,77]. However, although there is still controversy on the mechanism, a link to a-synuclein interaction with endophilin A or Rab proteins may reveal interesting new evidence related to Parkinson's pathology.…”

Section: [ 4 5 5 _ T D $ D I F F ] A-synuclein -A Possible Role In Slmentioning

confidence: 99%

See 1 more Smart Citation

α-Synuclein – Regulator of Exocytosis, Endocytosis, or Both?

Lautenschläger

Kaminski

Schierle

2017

Trends in Cell Biology

119

124

View full text Add to dashboard Cite

a-Synuclein is known as a presynaptic protein that binds to small synaptic vesicles. Recent studies suggest that a-synuclein is not only attracted to these tiny and therewith highly curved membranes, but that in fact the sensing and regulation of membrane curvature is part of its physiological function. Moreover, recent studies have suggested that a-synuclein plays a role in the endocytosis of synaptic vesicles, and have provided support for a function of a-synuclein during exo-and endocytosis in which curvature sensing and membrane stabilization are crucial steps. This review aims to highlight recent research in the field and adds a new picture on the function of a-synuclein in maintaining synaptic homeostasis upon intense and repetitive neuronal activity.

show abstract

Section: [ 4 5 5 _ T D $ D I F F ] A-synuclein -A Possible Role In Slsupporting

confidence: 66%

Section: [ 4 5 5 _ T D $ D I F F ] A-synuclein -A Possible Role In Slmentioning

confidence: 99%

α-Synuclein – Regulator of Exocytosis, Endocytosis, or Both?

Lautenschläger

Kaminski

Schierle

2017

Trends in Cell Biology

119

124

View full text Add to dashboard Cite

show abstract

“…LRRK2 has been described as regulating synaptic endocytosis via association with Rab5b; siRNA knockdown of LRRK2 markedly reduced synaptic vesicle endocytosis 122, which was reversed by the introduction of Rab5B. In mammalian cells, interaction was seen between LRRK2 and the dynamin GTPase superfamily 123 involved in membrane scission during clathrin‐associated endocytosis.…”

Section: Lrrk2 Function In Vesicle Dynamics and Retromer Functionmentioning

confidence: 99%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

View full text Add to dashboard Cite

Mutations in the leucine‐rich repeat kinase 2 (LRRK2)‐encoding gene are the most common cause of monogenic Parkinson's disease. The identification of LRRK2 polymorphisms associated with increased risk for sporadic Parkinson's disease, as well as the observation that LRRK2‐Parkinson's disease has a pathological phenotype that is almost indistinguishable from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic Parkinson's disease cases. LRRK2 is a large protein with both GTPase and kinase functions. Mutations segregating with Parkinson's disease reside within the enzymatic core of LRRK2, suggesting that modification of its activity impacts greatly on disease onset and progression. Although progress has been made since its discovery in 2004, there is still much to be understood regarding LRRK2′s physiological and neurotoxic properties. Unsurprisingly, given the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signalling pathways including mitochondrial function, vesicle trafficking together with endocytosis, retromer complex modulation and autophagy. This review discusses the state of current knowledge on the role of LRRK2 in health and disease with discussion of potential substrates of phosphorylation and functional partners with particular emphasis on signalling mechanisms. In addition, the use of immune cells in LRRK2 research and the role of oxidative stress as a regulator of LRRK2 activity and cellular function are also discussed.

show abstract

“…Rab5 is a small GTPase that acts as a key regulator of endocytic vesicular transport from the plasma membrane to early endosomes [68]. In culture experiments, Lrrk2 overexpression of WT or G2019S and R1441C mutants caused endocytosis deficits that were rescued by Rab5 but not by its inactive form [67]. This supports a role for Lrrk2 in synaptic function by modulating the endocytosis of synaptic vesicles.…”

Section: The Search For Interactors Of Lrrk2mentioning

confidence: 66%

“…With regard to Lrrk2 interactors and GTPase activity, a recent publication has shown that Lrrk2 interacts with Rab5 [67]. Rab5 is a small GTPase that acts as a key regulator of endocytic vesicular transport from the plasma membrane to early endosomes [68].…”

Section: The Search For Interactors Of Lrrk2mentioning

confidence: 99%

Update on the Functional Biology of Lrrk2

Melrose

2008

Future Neurol.

View full text Add to dashboard Cite

The etiology of Parkinson's disease (PD) was long thought to be due to environmental factors. Following the discovery of autosomal-dominant mutations in the α-synuclein gene, and later recessive mutations in the DJ-1, Parkin and PINK-1 genes, the field of PD genetics exploded. In 2004, it was discovered that mutations in the PARK8 locus -leucine-rich repeat kinase 2 (LRRK2, Lrrk2) -are the most important genetic cause of autosomal-dominant PD. Lrrk2 substitutions also account for sporadic PD in certain ethnic populations and have been shown to increase the risk of PD in Asian populations. Drug therapies targeting Lrrk2 activity may therefore be beneficial to both familial and sporadic PD patients, hence understanding the role of Lrrk2 in health and disease is critical. This review aims to highlight the research effort concentrated on elucidating the functional biological role of Lrrk2, and to provide some future therapeutic perspectives.

show abstract

LRRK2 regulates synaptic vesicle endocytosis

Cited by 309 publications

References 46 publications

α-Synuclein – Regulator of Exocytosis, Endocytosis, or Both?

α-Synuclein – Regulator of Exocytosis, Endocytosis, or Both?

Cellular processes associated with LRRK2 function and dysfunction

Update on the Functional Biology of Lrrk2

Contact Info

Product

Resources

About