RAB7L1 Interacts with LRRK2 to Modify Intraneuronal Protein Sorting and Parkinson’s Disease Risk

Departments of Pathology and Cell Biology, Columbia University, Black Building 1208, 650 West 168th Street, New York, NY 10032, USA.
Neuron (Impact Factor: 15.05). 02/2013; 77(3):425-39. DOI: 10.1016/j.neuron.2012.11.033
Source: PubMed


Recent genome-wide association studies have linked common variants in the human genome to Parkinson's disease (PD) risk. Here we show that the consequences of variants at 2 such loci, PARK16 and LRRK2, are highly interrelated, both in terms of their broad impacts on human brain transcriptomes of unaffected carriers, and in terms of their associations with PD risk. Deficiency of the PARK16 locus gene RAB7L1 in primary rodent neurons, or of a RAB7L1 ortholog in Drosophila dopamine neurons, recapitulated degeneration observed with expression of a familial PD mutant form of LRRK2, whereas RAB7L1 overexpression rescued the LRRK2 mutant phenotypes. PD-associated defects in RAB7L1 or LRRK2 led to endolysosomal and Golgi apparatus sorting defects and deficiency of the VPS35 component of the retromer complex. Expression of wild-type VPS35, but not a familial PD-associated mutant form, rescued these defects. Taken together, these studies implicate retromer and lysosomal pathway alterations in PD risk.

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    • "MacLeod et al. recently published a paper that demonstrates an interaction between Vps35 and another LRRK2 mutant, LRRK2(G2019S), where Vps35 protected against neuronal death caused by LRRK2(G2019S)[57]. Our data presented here independently validate these findings, and extend the relevance of these findings to two other pathogenic LRRK2 mutants, LRRK2(I2020T) and LRRK2(Y1699C), and one putative pathogenic mutant LRRK2(I1122V). "
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    ABSTRACT: Background Parkinson’s disease (PD) is the most common movement neurodegenerative movement disorder. An incomplete understanding of the molecular pathways involved in its pathogenesis impedes the development of effective disease-modifying treatments. To address this gap, we have previously generated a Drosophila model of PD that overexpresses PD pathogenic mutant form of the second most common causative gene of PD, Leucine-Rich Repeat Kinase 2 (LRRK2). Findings We employed this model in a genetic modifier screen and identified a gene that encodes for a core subunit of retromer – a complex essential for the sorting and recycling of specific cargo proteins from endosomes to the trans-Golgi network and cell surface. We present evidence that overexpression of the Vps35 or Vps26 component of the cargo-recognition subunit of the retromer complex ameliorates the pathogenic mutant LRRK2 eye phenotype. Furthermore, overexpression of Vps35 or Vps26 significantly protects from the locomotor deficits observed in mutant LRRK2 flies, as assessed by the negative geotaxis assay, and rescues their shortened lifespan. Strikingly, overexpressing Vps35 alone protects from toxicity of rotenone, a neurotoxin commonly used to model parkinsonism, both in terms of lifespan and locomotor activity of the flies, and this protection is sustained and even augmented in the presence of mutant LRRK2. Finally, we demonstrate that knocking down expression of Vps35 in dopaminergic neurons causes a significant locomotor impairment. Conclusions From these results we conclude that LRRK2 plays a role in the retromer pathway and that this pathway is involved in PD pathogenesis.
    Full-text · Article · Jun 2014 · Molecular Neurodegeneration
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    • "Each protein of the complex, which is likely formed using LRRK2 as a scaffold, contributes to the Golgi clearance function. One of them, the GTPase Rab7L1 (MacLeod et al., 2013; Beilina et al., 2014), is a cytosolic GTPase belonging to the Rab family of GTPases. This GTPase has been shown to localize at the Golgi and regulate the vesicular sorting (MacLeod et al., 2013). "
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    ABSTRACT: Neurological diseases have placed heavy social and financial burdens on modern society. As the life expectancy of humans is extended, neurological diseases, such as Parkinson's disease, have become increasingly common among senior populations. Although the enigmas of Parkinson's diseases await resolution, more vivid pictures on the cause, progression, and control of the illness are emerging after years of research. On the molecular level, GTPases are implicated in the etiology of Parkinson's disease and are rational pharmaceutical targets for their control. However, targeting individual GTPases, which belong to a superfamily of proteins containing multiple members with a conserved guanine nucleotide binding domain, has proven to be challenging. In contrast, pharmaceutical pursuit of inhibition of kinases, which constitute another superfamily of proteins with more than 500 members, has been fairly successful. We reviewed the breakthroughs in the history of kinase drug discovery to provide guidance for the GTPase field. We summarize recent progress made in the regulation of GTPase activity. We also present an efficient and cost effective approach to drug screening, which uses multiplex flow cytometry and mixture-based positional scanning libraries. These methods allow simultaneous measurements of both the activity and the selectivity of the screened library. Several GTPase activator clusters were identified which showed selectivity against different GTPase subfamilies. While the clusters need to be further deconvoluted to identify individual active compounds, the method described here and the structure information gathered create a foundation for further developments to build upon.
    Full-text · Article · Jun 2014 · Frontiers in Molecular Neuroscience
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    • "There are multiple evidences for a link between LRRK2 and rab7. For example, rab7 overexpression also rescues the neurite outgrowth phenotype of mutant LRRK2 in vitro, and dopamine neuron loss and lethality in vivo (MacLeod et al., 2013). Whilst rab7 can modulate retromer function (Rojas et al., 2008), it is better known for its action as a multifunctional regulator of endocytosis and autophagy at various distinct steps, including endosomal and autophagosomal maturation, motility of late endosomes/autophagosomes on microtubules, and eventual fusion with lysosomes (Fig. 5) (reviewed in Hyttinen et al., 2013). "
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    ABSTRACT: Mutations in LRRK2 (leucine-rich repeat kinase 2) are found associated with both sporadic and familial Parkinson´s disease (PD). Pathogenic mutations are localized to the catalytic domains of LRRK2, including kinase and GTPase domains. Altered catalytic activity correlates with neurotoxicity, indicating that targeting those activities may provide clues as to novel therapeutic strategies for LRRK2-linked PD. However, the cellular readout of such altered catalytic activities remains largely unknown. Recent cell biological studies have started to highlight possible early cellular events which are altered in the presence of pathogenic LRRK2 and may ultimately lead to neuronal demise, and these studies link altered LRRK2 function to various abnormal endolysosomal vesicular trafficking events. This review examines our current knowledge of LRRK2 neurobiology and how pathogenic mutations may lead to neurodegeneration in PD.
    Full-text · Article · May 2014 · Neuropharmacology
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