Pathogenic Parkinson’s disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation

Manzoni, Claudia; Mamais, Adamantios; Dihanich, Sybille; McGoldrick, Phillip; Devine, Michael J.; Zerle, Julia; Kara, Eleanna; Taanman, Jan‐Willem; Healy, Daniel G.; Martí-Massó, J F; Schapira, Anthony H.V.; Plun‐Favreau, Hélène; Tooze, Sharon A.; Hardy, John; Bandopadhyay, Rina; Lewis, Patrick A.

doi:10.1016/j.bbrc.2013.10.159

Cited by 76 publications

(69 citation statements)

References 33 publications

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“…Via interactions with multiple molecules, leucine-rich repeat kinase 2 (LRRK2) functions in apoptosis (10), protein synthesis (11,12), and cytoskeletal dynamics (13)(14)(15). Recently, several reports have demonstrated that LRRK2 controls autophagy (16)(17)(18)(19)(20). Owing to this diversity of function, despite intense interest and extensive study, the mechanisms by which LRRK2 mutations cause neurodegeneration remain unclear.…”

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confidence: 99%

Leucine-Rich Repeat Kinase 1 Regulates Autophagy through Turning On TBC1D2-Dependent Rab7 Inactivation

Toyofuku

Morimoto

Sasawatari

et al. 2015

Molecular and Cellular Biology

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bAutophagy is a conserved process that enables catabolic and degradative pathways. Rab family proteins, which are active in the GTP-bound form, regulate the transport and fusion of autophagosomes. However, it remains unclear how each cycle of Rab activation and inactivation is precisely regulated. Here, we show that leucine-rich repeat kinase 1 (LRRK1) regulates autophagic flux by controlling Rab7 activity in autolysosome formation. Upon induction of autophagy, LRRK1 was recruited via an association with VAMP7 to the autolysosome, where it activated the Rab7 GTPase-activating protein (GAP) TBC1D2, thereby switching off Rab7 signaling. Consistent with this model, LRRK1 deletion caused mice to be vulnerable to starvation and disrupted autolysosome formation, as evidenced by the accumulation of enlarged autolysosomes with undegraded LC3-II and persistently high levels of Rab7-GTP. This defect in autophagic flux was partially rescued by a mutant form of TBC1D2 with elevated Rab7-GAP activity. Thus, the spatiotemporal regulation of Rab7 activity during tunicamycin-induced autophagy is regulated by LRRK1.

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confidence: 99%

Leucine-Rich Repeat Kinase 1 Regulates Autophagy through Turning On TBC1D2-Dependent Rab7 Inactivation

Toyofuku

Morimoto

Sasawatari

et al. 2015

Molecular and Cellular Biology

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“…Even though the brain of LRRK2 knockout mice did not recapitulate the pathological hallmarks of PD, a biphasic alteration in macroautophagy has been observed in the kidneys, with enhanced autophagy at young ages and reduced autophagy at old ages 112. The use of human fibroblasts carrying LRRK2 pathogenic mutations has confirmed an alteration in autophagy with reports suggesting an increase in basal macroautophagy in G2019S carriers 113, or an impaired response to starvation‐induced macroautophagy across mutations in the LRRK2 catalytic core ( G2019S , Y1699C and R1441G ) 114. The use of induced Pluripotent Stem cell (iPSC)‐derived, human dopaminergic neurons carrying G2019S ‐LRRK2 has confirmed a reduction in macroautophagy in comparison with healthy controls 115; but again, details of the molecular mechanism underlying this are still ambiguous.…”

Section: Lrrk2 and Autophagymentioning

confidence: 96%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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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.

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“…This effect is presumably related to the known function of LRRK2 in autophagy (18,24,33,37,38) but can be tied mechanistically to disruption of TGN. Interestingly, autophagic vesicles may derive from the trans-Golgi network (37); hence, altered turnover of Golgi-derived vesicles would impact autophagy function over time, consistent with effects of LRRK2 deficiency in animal models (34).…”

Section: Discussionmentioning

confidence: 99%

Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease

Beilina¹,

Rudenko²,

Kaganovich³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Understanding loci nominated by genome-wide association studies (GWASs) is challenging. Here, we show, using the specific example of Parkinson disease, that identification of protein–protein interactions can help determine the most likely candidate for several GWAS loci. This result illustrates a significant general principle that will likely apply across multiple diseases.

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Pathogenic Parkinson’s disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation

Abstract: HighlightsMutations in the ROC, COR and Kinase domain of LRRK2 alter the autophagic response to starvation.LC3-I/II ratio following starvation is altered by mutations, as well as p62 and WIPI2 positive puncta.This occurs independently of any alteration in downstream targets of mTORC1.

Cited by 76 publications

References 33 publications

Leucine-Rich Repeat Kinase 1 Regulates Autophagy through Turning On TBC1D2-Dependent Rab7 Inactivation

Leucine-Rich Repeat Kinase 1 Regulates Autophagy through Turning On TBC1D2-Dependent Rab7 Inactivation

Cellular processes associated with LRRK2 function and dysfunction

Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease

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