Association study of <i>DNAJC13, UCHL1, HTRA2, GIGYF2</i> and <i>EIF4G1</i> with Parkinson’s disease

Saini, Prabhjyot; Rudakou, Uladzislau; Yu, Eric; Ruskey, Jennifer A.; Asayesh, Farnaz; Laurent, Sandra B.; Spiegelman, Dan; Fahn, Stanley; Waters, Cheryl; Monchi, Oury; Dauvilliers, Yves; Dupré, Nicolas; Greenbaum, Lior; Hassin‐Baer, Sharon; Espay, Alberto J.; Rouleau, Guy A.; Alcalay, Roy N.; Fon, Edward A.; Postuma, Ronald B.; Gan‐Or, Ziv

doi:10.1101/2020.06.26.20141176

Cited by 4 publications

(3 citation statements)

References 78 publications

(92 reference statements)

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“…2 A) [ 15 ]. The detected transport proteins also included endosomal trafficking-related proteins, such as DnaJ homolog subfamily C member 13 (DNAJC13) [ 16 , 17 ] (Fig. 2 A), which is involved in membrane trafficking through early endosomes and implicated in recycling epidermal growth factor receptor.…”

Section: Resultsmentioning

confidence: 99%

Proteomic analysis of bone marrow-derived mesenchymal stem cell extracellular vesicles from healthy donors: implications for proliferation, angiogenesis, Wnt signaling, and the basement membrane

et al. 2021

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Background Bone marrow-derived mesenchymal stem cells (BM-MSCs) have shown therapeutic potential in various in vitro and in vivo studies in cutaneous wound healing. Furthermore, there are ubiquitous studies highlighting the pro-regenerative effects of BM-MSC extracellular vesicles (BM-MSC EVs). The similarities and differences in BM-MSC EV cargo among potential healthy donors are not well understood. Variation in EV protein cargo is important to understand, as it may be useful in identifying potential therapeutic applications in clinical trials. We hypothesized that the donors would share both important similarities and differences in cargo relating to cell proliferation, angiogenesis, Wnt signaling, and basement membrane formation—processes shown to be critical for effective cutaneous wound healing. Methods We harvested BM-MSC EVs from four healthy human donors who underwent strict screening for whole bone marrow donation and further Good Manufacturing Practices-grade cell culture expansion for candidate usage in clinical trials. BM-MSC EV protein cargo was determined via mass spectrometry and Proteome Discoverer software. Corresponding proteomic networks were analyzed via the UniProt Consortium and STRING consortium databases. Results More than 3000 proteins were identified in each of the donors, sharing > 600 proteins among all donors. Despite inter-donor variation in protein identities, there were striking similarities in numbers of proteins per biological functional category. In terms of biologic function, the proteins were most associated with transport of ions and proteins, transcription, and the cell cycle, relating to cell proliferation. The donors shared essential cargo relating to angiogenesis, Wnt signaling, and basement membrane formation—essential processes in modulating cutaneous wound repair. Conclusions Healthy donors of BM-MSC EVs contain important similarities and differences among protein cargo that may play important roles in their pro-regenerative functions. Further studies are needed to correlate proteomic signatures to functional outcomes in cutaneous repair.

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Section: Resultsmentioning

confidence: 99%

Proteomic analysis of bone marrow-derived mesenchymal stem cell extracellular vesicles from healthy donors: implications for proliferation, angiogenesis, Wnt signaling, and the basement membrane

et al. 2021

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“…It is possible that this variant is associated with a specific form of atypical parkinsonism, but not with typical PD. It has been shown that a number of genes previously reported as PD-associated (such as DNAJC13, UCHL1, HTRA2, GIGYF2 , and EIF4G1 ) do not play a role in PD and thus, should not be regarded as PD genes (Foo et al, 2014; Krüger et al, 2011; Lesage et al, 2010; Saini et al, 2020). Furthermore, other genes (e.g.…”

Section: Discussionmentioning

confidence: 99%

Lack of evidence for association of UQCRC1 with Parkinson’s disease in Europeans

Senkevich

Bandrés‐Ciga

Gan‐Or

et al. 2020

Preprint

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Recently, a novel variant p.Y314S in UQCRC1 has been implicated as pathogenic in Parkinson′ s disease (PD). In the current study, we aimed to examine the association of UQCRC1 with PD in large cohorts of European origin. We examined common and rare genetic variation in UQCRC1 using genome-wide association study data from the International Parkinson Disease Genomics Consortium (IPDGC), including 14,671 cases and 17,667 controls, and whole-genome sequencing data from the Accelerating Medicines Partnership - Parkinson′ s disease initiative (AMP-PD), including 1,647 PD patients and 1,050 controls. No common variants were consistently associated with PD, and a variety of burden analyses did not reveal an association between rare variants in UQCRC1 and PD. Therefore, our results do not support a major role for UQCRC1 in PD in the European population, and additional studies in other populations are warranted.

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“…The copyright holder for this preprint (which this version posted April 12, 2023. ; https://doi.org /10.1101/2023.04.11.536367 doi: bioRxiv preprint revealed single nucleotide variants (SNVs) in PD-relevant genes for some LCL lines (Table 2). Amongst the idiopathic PD lines which displayed a centrosomal cohesion deficit, one line harboured a variant in the translational repressor GIGYF2, a gene at the PARK11 locus with an unconfirmed link to PD (56,57). Amongst the PD lines without a cohesion deficit, one displayed a variant in ATP13A2, and two displayed a known pathogenic missense mutation in PRKN (Table 2).…”

Section: Identification Of Gene Variants In Idiopathic Pd Samplesmentioning

confidence: 99%

A potential patient stratification biomarker for Parkinso’s disease based on LRRK2 kinase-mediated centrosomal alterations in peripheral blood-derived cells

Naaldijk

Fernández

Fasiczka

et al. 2023

Preprint

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Parkinson's disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for disease intervention. However, the ability to stratify patients who will benefit from such treatment modalities based on shared etiology is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types. We previously found centrosomal deficits in immortalized lymphocytes from G2019S-LRRK2 PD patients. Here, to investigate whether such deficits may serve as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we characterized patient-derived cells from distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early-stage idiopathic PD patients which is mitigated by LRRK2 kinase inhibition, supporting a role for aberrant LRRK2 activity in idiopathic PD. Centrosomal defects are detected in R1441G-LRRK2 and G2019S-LRRK2 PD patients and in non-manifesting LRRK2 mutation carriers, indicating that they acumulate prior to a clinical PD diagnosis. They are present in immortalized cells as well as in primary lymphocytes from peripheral blood. These findings indicate that analysis of centrosomal defects as a blood-based patient stratification biomarker may help nominate PD patients who will benefit from LRRK2-related therapeutics.

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Association study of DNAJC13, UCHL1, HTRA2, GIGYF2 and EIF4G1 with Parkinson’s disease

Cited by 4 publications

References 78 publications

Proteomic analysis of bone marrow-derived mesenchymal stem cell extracellular vesicles from healthy donors: implications for proliferation, angiogenesis, Wnt signaling, and the basement membrane

Proteomic analysis of bone marrow-derived mesenchymal stem cell extracellular vesicles from healthy donors: implications for proliferation, angiogenesis, Wnt signaling, and the basement membrane

Lack of evidence for association of UQCRC1 with Parkinson’s disease in Europeans

A potential patient stratification biomarker for Parkinso’s disease based on LRRK2 kinase-mediated centrosomal alterations in peripheral blood-derived cells

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