Parkinson's disease-associated mutant LRRK2 phosphorylates Rab7L1 and modifies trans-Golgi morphology

Fujimoto, Tetta; Kuwahara, Tomohiro; Eguchi, Tomohiro; Sakurai, Maria; Komori, Tadayuki; Iwatsubo, Takeshi

doi:10.1016/j.bbrc.2017.12.024

Cited by 76 publications

(88 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, the data from this study reinforces that status of the RAB29 gene as the priority candidate for the chromosome 1q32 locus association. Recent studies providing further functional evidence linking RAB29 (aka RAB7L1 ) to LRRK2 , and implicating RAB29 as a substrate for LRRK2 kinase activity, also support this designation (Fujimoto et al , 2018; Liu et al , 2018; Purlyte et al , 2018). Interestingly, in the GPNMB/NUPL2 locus, the PD GWAS results suggest only one independent signal, while the results presented in this paper nominate both GPNMB (gene level) and NUPL2 (splicing) with strong PPI evidence connecting both to Mendelian or sporadic risk genes.…”

Section: Discussionmentioning

confidence: 81%

Integration of eQTL and Parkinson’s disease GWAS data implicates 11 disease genes

Kia

Zhang

Guelfi

et al. 2019

Preprint

View full text Add to dashboard Cite

Substantial genome-wide association study (GWAS) work in Parkinson's disease (PD) has led to an increasing number of loci shown reliably and robustly to be associated with the increased risk of the disease. Prioritising causative genes and pathways from these studies has proven problematic. Here, we present a comprehensive analysis of PD GWAS data with expression and methylation quantitative trait loci (eQTL/mQTL) using Colocalisation analysis (Coloc) and transcriptome-wide association analysis (TWAS) to uncover putative gene expression and splicing mechanisms driving PD GWAS signals.Candidate genes were further characterised by determining cell-type specificity, weighted gene coexpression (WGNCA) and protein-protein interaction (PPI) networks.Gene-level analysis of expression revealed 5 genes (WDR6, CD38, GPNMB, RAB29, TMEM163) that replicated using both Coloc and TWAS analyses in both GTEx and Braineac expression datasets. A further 6 genes (ZRANB3, PCGF3, NEK1, NUPL2, GALC, CTSB) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell-types compared to neurons. The WGNCA analysis showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes related with protein ubiquitination (protein ubiquitination (p=7.47e-10) and ubiquitin-dependent protein catabolic process (p = 2.57e-17) in nucleus accumbens, caudate and putamen, while TMEM163 and ZRANB3 were both important in modules indicating regulation of signalling (p=1.33e-65] and cell communication (p=7.55e-35) in the frontal cortex and caudate respectively. PPI analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known Mendelian PD and parkinsonism proteins than would be expected by chance. The proteins core proteins this network were enriched for regulation of the ERBB receptor tyrosine protein kinase signalling pathways.Together, these results point to a number of candidate genes and pathways that are driving the associations observed in PD GWAS studies.

show abstract

Section: Discussionmentioning

confidence: 81%

Integration of eQTL and Parkinson’s disease GWAS data implicates 11 disease genes

Kia

Zhang

Guelfi

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Prior literature suggests that LRRK2 and RAB29 operate within the same genetic pathway (Purlyte et al, 2018;Gomez et al, 2019; for review, see Taylor & Alessi, 2020). LRRK2 can phosphorylate membrane bound RAB29, which is normally resident at the trans-Golgi network (TGN; Steger et al, 2017;Fujimoto et al, 2018;Gomez et al, 2019). This interaction indicates that RAB29 is a downstream effector of LRRK2, where it may mediate alterations in membrane trafficking and neurite outgrowth (Kuwahara et al, 2016;Feng et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…While mutations at the LRRK2 and RAB29 loci are independently associated with increased PD risk, there is evidence suggesting a genetic interaction between the two genes (Pihlstrom et al, 2015). Additionally, LRRK2 phosphorylates RAB29 when RAB29 is membrane and GTP bound (Steger et al, 2017;Fujimoto et al, 2018;Liu et al, 2018). PDrelated LRRK2 mutations exacerbate RAB29 phosphorylation (Steger et al, 2017;Lis et al, 2018), suggesting relevance to familial PD.…”

Section: Introductionmentioning

confidence: 99%

Combined knockout ofLrrk2andRab29does not result in behavioral abnormalitiesin vivo

Mazza

Nguyen

Beilina

et al. 2020

Preprint

View full text Add to dashboard Cite

Coding mutations in the LRRK2 gene, encoding for a large protein kinase, have been shown to cause familial Parkinson's disease (PD). The immediate biological consequence of LRRK2 mutations is to increase kinase activity, leading to the suggestion that inhibition of this enzyme might be useful therapeutically to slow disease progression. Genome-wide association studies have identified the chromosomal loci around LRRK2 and one of its proposed substrates, RAB29, as contributors towards the lifetime risk of sporadic PD. Considering the evidence for interactions between LRRK2 and RAB29 on the genetic and protein levels, here we generated a double knockout mouse model and determined whether there are any consequences on brain function with aging. From a battery of motor and non-motor behavioral tests, we noted only that 18-24 month Rab29 -/and double (Lrrk2 -/-/Rab29 -/-) knockout mice had diminished locomotor behavior in open field compared to wildtype mice. However, no genotype differences were seen in number of substantia nigra pars compacta (SNc) dopamine neurons or in tyrosine hydroxylase levels in the SNc and striatum, which might reflect a PD-like pathology. These results suggest that depletion of both Lrrk2 and Rab29 is tolerated, at least in mice, and support that this pathway might be able to be safely targeted for therapeutics in humans. Significance statement:Genetic variation in LRRK2 that result in elevated kinase activity can cause Parkinson's disease (PD), suggesting LRRK2 inhibition as a therapeutic strategy. RAB29, a substrate of LRRK2, has also been associated with increased PD risk. Evidence exists for an interactive relationship between LRRK2 and RAB29. Mouse models lacking either LRRK2 or RAB29 do not show brain pathologies. We hypothesized that the loss of both targets would result in additive effects across in vivo and post-mortem assessments in aging mice. We found that loss of both LRRK2 and RAB29 did not result in significant behavioral deficits or dopamine neuron loss. This evidence suggests that chronic inhibition of this pathway should be tolerated clinically.

show abstract

“…The primary effect of α-synuclein aggregation is the inhibition of ER-to-Golgi transport (Lashuel and Hirling 2006), which can be rescued by the overexpression of Rab1 and Rab8 and depletion of Rab2 and syntaxin 5 (Rendon et al 2013;Coune et al 2011). In a most recent report, mutations in the leucine-rich repeat kinase 2 (LRRK2), a major genetic cause of autosomaldominantly inherited PD, markedly enhance Rab7L1 phosphorylation on S72, resulting in TGN fragmentation (Fujimoto et al 2018).…”

Section: Parkinson's Disease (Pd)mentioning

confidence: 99%

Golgi Structure and Function in Health, Stress, and Diseases

Ahat

Wang

2019

Results and Problems in Cell Differentiation

View full text Add to dashboard Cite

The Golgi apparatus is a central intracellular membrane-bound organelle with key functions in trafficking, processing, and sorting of newly synthesized membrane and secretory proteins and lipids. To best perform these functions, Golgi membranes form a unique stacked structure. The Golgi structure is dynamic but tightly regulated; it undergoes rapid disassembly and reassembly during the cell cycle of mammalian cells and is disrupted under certain stress and pathological conditions. In the past decade, significant amount of effort has been made to reveal the molecular mechanisms that regulate the Golgi membrane architecture and function. Here we review the major discoveries in the mechanisms of Golgi structure formation, regulation, and alteration in relation to its functions in physiological and pathological conditions to further our understanding of Golgi structure and function in health and diseases.

show abstract

Parkinson's disease-associated mutant LRRK2 phosphorylates Rab7L1 and modifies trans-Golgi morphology

Cited by 76 publications

References 29 publications

Integration of eQTL and Parkinson’s disease GWAS data implicates 11 disease genes

Integration of eQTL and Parkinson’s disease GWAS data implicates 11 disease genes

Combined knockout ofLrrk2andRab29does not result in behavioral abnormalitiesin vivo

Golgi Structure and Function in Health, Stress, and Diseases

Contact Info

Product

Resources

About