RAB3 phosphorylation by pathogenic LRRK2 impairs trafficking of synaptic vesicle precursors DOI Creative Commons
Dan Dou, Jayne Aiken, Erika L.F. Holzbaur

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 25, 2023

ABSTRACT Gain-of-function mutations in the LRRK2 gene cause Parkinson’s disease (PD), characterized by debilitating motor and non-motor symptoms. Increased phosphorylation of a subset RAB GTPases is implicated PD pathogenesis. We find that increased RAB3A, cardinal synaptic vesicle precursor (SVP) protein, disrupts anterograde axonal transport SVPs iPSC-derived human neurons (iNeurons) expressing hyperactive -p.R1441H. Knockout opposing protein phosphatase 1H ( PPM1H ) iNeurons phenocopies this effect. In these models, compartmental distribution proteins altered; synaptophysin synaptobrevin-2 become sequestered neuronal soma with decreased delivery to presynaptic sites along axon. RAB3A binding adapter MADD, potentially preventing formation RAB3A-MADD-KIF1A/1Bβ complex driving SVP transport. hyperphosphorylation also interactions RAB3GAP RAB-GDI1. Our results reveal mechanism which pathogenic may contribute altered homeostasis associated characteristic cognitive manifestations PD. SUMMARY Dou et al. demonstrate disease-associated decreases trafficking within disrupting regulation RAB3A. Impaired could progression

Language: Английский

Pathogenesis of Parkinson’s Disease DOI
Bin Xiao, Zhidong Zhou, Yinxia Chao

et al.

Neurologic Clinics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

2
CURTAIN—A unique web-based tool for exploration and sharing of MS-based proteomics data DOI Creative Commons
Toan K. Phung, Kerryn Berndsen, R. Shastry

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(7)

Published: Feb. 7, 2024

To facilitate analysis and sharing of mass spectrometry (MS)-based proteomics data, we created online tools called CURTAIN (https://curtain.proteo.info) CURTAIN-PTM (https://curtainptm.proteo.info) with an accompanying series video tutorials (https://www.youtube.com/@CURTAIN-me6hl). These are designed to enable non-MS experts interactively peruse volcano plots deconvolute primary experimental data so that replicates can be visualized in bar charts or violin exported publication-ready format. They also allow assessment overall quality by correlation matrix profile plot analysis. After making a selection protein "hits", the user analyze known domain structure, AlphaFold predicted reported interactors, relative expression as well disease links. permits all identified PTM sites on protein(s) interest selected databases. links Kinase Library predict upstream kinases may phosphorylate interest. We provide examples utility analyzing how targeted degradation PPM1H Rab phosphatase counteracts Parkinson's LRRK2 kinase impacts cellular levels phosphorylation sites. reanalyzed ubiquitylation dataset, characterizing PINK1-Parkin pathway activation neurons, revealing not highlighted previously. free use open source, enabling researchers share maximize impact their data. advocate MS published format containing shareable weblink, thereby allowing readers better exploit

Language: Английский

Citations

9
RAB3 phosphorylation by pathogenic LRRK2 impairs trafficking of synaptic vesicle precursors DOI Creative Commons
Dan Dou, Jayne Aiken, Erika L.F. Holzbaur

et al.

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(6)

Published: March 21, 2024

Gain-of-function mutations in the LRRK2 gene cause Parkinson’s disease (PD), characterized by debilitating motor and non-motor symptoms. Increased phosphorylation of a subset RAB GTPases is implicated PD pathogenesis. We find that increased RAB3A, cardinal synaptic vesicle precursor (SVP) protein, disrupts anterograde axonal transport SVPs iPSC-derived human neurons (iNeurons) expressing hyperactive LRRK2-p.R1441H. Knockout opposing protein phosphatase 1H (PPM1H) iNeurons phenocopies this effect. In these models, compartmental distribution proteins altered; synaptophysin synaptobrevin-2 become sequestered neuronal soma with decreased delivery to presynaptic sites along axon. RAB3A binding adaptor MADD, potentially preventing formation RAB3A–MADD-KIF1A/1Bβ complex driving SVP transport. hyperphosphorylation also interactions RAB3GAP RAB-GDI1. Our results reveal mechanism which pathogenic may contribute altered homeostasis associated characteristic cognitive manifestations PD.

Language: Английский

Citations

7
LRRK2 in Parkinson's disease: upstream regulation and therapeutic targeting DOI
Yulan Xiong, Jianzhong Yu

Trends in Molecular Medicine, Journal Year: 2024, Volume and Issue: 30(10), P. 982 - 996

Published: Aug. 16, 2024

Language: Английский

Citations

7
Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain DOI Creative Commons
Enrico Bagnoli, Yu‐En Lin, Sophie Burel

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(5)

Published: Jan. 28, 2025

Mutations in Leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced 1 (PINK1) are associated with familial Parkinson’s disease (PD). LRRK2 phosphorylates Rab guanosine triphosphatase (GTPases) within the Switch II domain while PINK1 directly Parkin ubiquitin (Ub) indirectly induces phosphorylation of a subset GTPases. Herein we have crossed [R1441C] mutant knock-in mice knock-out (KO) report that loss does not impact endogenous LRRK2-mediated nor do see significant effect on PINK1-mediated Ub phosphorylation. In addition, observe pool Rab-specific, protein phosphatase family member 1H phosphatase, is transcriptionally up-regulated recruited to damaged mitochondria, independent or activity. Parallel signaling pathways supported by assessment motor behavioral studies show no evidence genetic interaction mouse lines. Previously showed cilia R1441C herein KO exhibit ciliogenesis defect striatal cholinergic interneurons astrocytes interferes Hedgehog induction glial derived-neurotrophic factor transcription. This exacerbated double-mutant mice. Overall, our analysis indicates activation and/or function along parallel impair ciliogenesis, suggesting convergent mechanism toward PD. Our data suggest reversal defects downstream offers common therapeutic strategy for PD patients, whereas inhibitors currently clinical trials unlikely benefit patients.

Language: Английский

Citations

0
Leucine-Rich Repeat Kinase 1 Signaling Targets Proteins Critical for Endosome/Lysosome Sorting and Trafficking in Osteoclasts DOI Creative Commons
Weirong Xing, Yi‐An Chen,

Anakha Udayakumar

et al.

Biology, Journal Year: 2025, Volume and Issue: 14(4), P. 326 - 326

Published: March 24, 2025

Global knockout (KO) of the Lrrk1 gene in mice causes severe osteopetrosis because failure osteoclasts to resorb bone. The molecular mechanism LRRK1 regulation osteoclast function is not fully understood. Here, we performed a 2D DIGE phosphor-proteomics analysis identify potential targets osteoclasts. Splenocytes from KO and wild-type (WT) were differentiated into for protein extraction. Lysates WT cells labeled with Cy3- Cy5-dye, respectively. Labeled proteins mixed analyzed on same SDS PAGE profiling. amounts cellular also Cy3-dye ran PAGE. gels then stained using Pro-Q® Diamond Phosphoprotein Gel Stain phosphoprotein Differentially phosphorylated spots between two types collected, digested trypsin, identified by mass spectrometry. Seventeen phosphoproteins identified, six which are known be involved endosome/lysosome sorting, vacuolar protection, trafficking. While five these (SNX2, VPS35, VTA1, CFL1, CTSA) significantly hypophosphorylated, SNX3 was hyperphosphorylated LRRK1-deficient downregulation VSP35 CFL1 phosphorylation validated Phos-tag analysis. Our results indicate that signaling regulates via modulating VPS35 critical trafficking dynamic cytoskeleton arrangement

Language: Английский

Citations

0
Immune cell metabolic dysfunction in Parkinson’s disease DOI Creative Commons
Julian R Mark, Malú G. Tansey

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 24, 2025

Abstract Parkinson’s disease (PD) is a multi-system disorder characterized histopathologically by degeneration of dopaminergic neurons in the substantia nigra pars compacta . While etiology PD remains multifactorial and complex, growing evidence suggests that cellular metabolic dysfunction critical driver neuronal death. Defects metabolism related to energy production, oxidative stress, organelle health, protein homeostasis have been reported both immune cells PD. We propose these factors act synergistically drive aberrant inflammation CNS periphery PD, contributing hostile inflammatory environment which renders certain subsets vulnerable degeneration. This review highlights overlap between established deficits with emerging findings central peripheral cells. By discussing rapidly expanding literature on immunometabolic we aim draw attention potential biomarkers facilitate future development immunomodulatory strategies prevent or delay progression

Language: Английский

Citations

0
TMEM55A-mediated PI5P signalling regulates alpha cell actin depolymerisation and glucagon secretion DOI Creative Commons
Xiong Liu, Theodore dos Santos, Aliya F Spigelman

et al.

Diabetologia, Journal Year: 2025, Volume and Issue: unknown

Published: March 26, 2025

Language: Английский

Citations

0
Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine physiology in VPS35 p.D620N knock-in mice DOI Creative Commons
Mengfei Bu, Jordan Follett, Isaac Deng

et al.

npj Parkinson s Disease, Journal Year: 2023, Volume and Issue: 9(1)

Published: Dec. 18, 2023

Dysregulation of dopamine neurotransmission profoundly affects motor, motivation and learning behaviors, can be observed during the prodromal phase Parkinson's disease (PD). However, mechanism underlying these pathophysiological changes remains to elucidated. Mutations in vacuolar protein sorting 35 (VPS35) leucine-rich repeat kinase 2 (LRRK2) both lead autosomal dominant PD, VPS35 LRRK2 may physically interact govern trafficking synaptic cargos within endo-lysosomal network a kinase-dependent manner. To better understand functional role on physiology, we examined Vps35 haploinsufficient (Haplo) p.D620N knock-in (VKI) mice how their behavior, kinetics biochemistry are influenced by inhibitors. We found significantly elevates LRRK2-mediated phosphorylation Rab10, Rab12 Rab29. In contrast, haploinsufficiency reduces Rab12. While striatal transporter (DAT) expression function is similarly impaired VKI Haplo mice, that physiology normalized treatment with inhibitor, MLi-2. As corollary, animals show significant increase amphetamine induced hyperlocomotion, compared also abolished Taken together, data confers gain-of-function respect activity, functionally regulate DAT transmission.

Language: Английский

Citations

8
Opposing actions of JIP4 and RILPL1 provide antagonistic motor force to dynamically regulate membrane reformation during lysosomal tubulation/sorting driven by LRRK2 DOI Creative Commons
Luis Bonet‐Ponce,

Tsion Tegicho,

Alexandra Beilina

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 3, 2024

ABSTRACT Lysosomes are dynamic cellular structures that adaptively remodel their membrane in response to stimuli, including damage. We previously uncovered a process we term LYTL (LYsosomal Tubulation/sorting driven by Leucine-Rich Repeat Kinase 2 [LRRK2]), wherein damaged lysosomes generate tubules sorted into mobile vesicles. is orchestrated the Parkinson’s disease-associated kinase LRRK2 recruits motor adaptor protein and RHD family member JIP4 via phosphorylated RAB proteins. To identify new players involved LYTL, performed unbiased proteomics on isolated after inhibition. Our results demonstrate there recruitment of RILPL1 ruptured activity promote phosphorylation proteins at lysosomal surface. RILPL1, which also family, enhances clustering LRRK2-positive perinuclear area causes retraction tubules, contrast promotes tubule extension. Mechanistically, binds p150 Glued , dynactin subunit, facilitating transport minus end microtubules. Further characterization tubulation revealed move along tyrosinated microtubules, with tubulin tyrosination proving essential for elongation. In summary, our findings emphasize regulation two distinct pRAB effectors, serving as opposing proteins: JIP4, promoting kinesin, through dynein/dynactin. infer processes metastable deformation facilitates events.

Language: Английский

Citations

2