Regulators of proteostasis are translationally repressed in fibroblasts from patients with sporadic and LRRK2-G2019S Parkinson’s disease

Flinkman, Dani; Yun, Hong Shik; Gnjatovic, Jelena; Deshpande, Prasannakumar; Ortutay, Zsuzsanna; Peltonen, Sirkku; Kaasinen, Valtteri; James, Peter; Coffey, Eleanor T.

doi:10.1038/s41531-023-00460-w

Cited by 9 publications

(6 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Activated PKR leads to eIF2α phosphorylation, and results in global protein synthesis attenuation 81 . Protein synthesis is reduced in PD patient cell lines 91 , 92 , consistent with the reduced expression of genes related to protein synthesis and ribosomal function we observed in PD (Fig. 2c , Supplementary Data 2 , 3 ).…”

Section: Discussionsupporting

confidence: 86%

Early-stage idiopathic Parkinson’s disease is associated with reduced circular RNA expression

Whittle,

Izuogu,

Lowes

et al. 2024

npj Parkinsons Dis.

View full text Add to dashboard Cite

Neurodegeneration in Parkinson’s disease (PD) precedes diagnosis by years. Early neurodegeneration may be reflected in RNA levels and measurable as a biomarker. Here, we present the largest quantification of whole blood linear and circular RNAs (circRNA) in early-stage idiopathic PD, using RNA sequencing data from two cohorts (PPMI = 259 PD, 161 Controls; ICICLE-PD = 48 PD, 48 Controls). We identified a replicable increase in TMEM252 and LMNB1 gene expression in PD. We identified novel differences in the expression of circRNAs from ESYT2, BMS1P1 and CCDC9, and replicated trends of previously reported circRNAs. Overall, using circRNA as a diagnostic biomarker in PD did not show any clear improvement over linear RNA, minimising its potential clinical utility. More interestingly, we observed a general reduction in circRNA expression in both PD cohorts, accompanied by an increase in RNASEL expression. This imbalance implicates the activation of an innate antiviral immune response and suggests a previously unknown aspect of circRNA regulation in PD.

show abstract

Section: Discussionsupporting

confidence: 86%

Early-stage idiopathic Parkinson’s disease is associated with reduced circular RNA expression

Whittle,

Izuogu,

Lowes

et al. 2024

npj Parkinsons Dis.

View full text Add to dashboard Cite

show abstract

“…48 Other deficits included KARS1, a tRNA synthetase; PSMC5, the proteasomal 26S subunit; or SCLY, seleno-cysteine lyase, an enzyme involved in peptide elongation that is also involved in neurodegeneration. 64 Our findings in LRRK2 PMBCs align with studies reporting transcriptional repression of proteostasis regulators in G2019S L2PD, 65 and proteostasis defects in PD substantia nigra. 66 R1441G L2PD showed 80 differential proteins with 40% shared with G2019S L2PD.…”

Section: Discussionsupporting

confidence: 85%

In-depth mass-spectrometry reveals phospho-RAB12 as a blood biomarker of G2019S LRRK2-driven Parkinson’s

Cortés,

Phung,

de Mena

et al. 2024

Preprint

View full text Add to dashboard Cite

Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising disease-modifying therapy for LRRK2-associated Parkinson disease (L2PD) and idiopathic PD (iPD). Yet, pharmaco-dynamic readouts and progression biomarkers for disease modification clinical trials are insufficient. Employing phospho-/proteomic analyses we assessed the impact that LRRK2 activating mutations had in peripheral blood mononuclear cells (PBMCs) from a LRRK2 clinical cohort from Spain (n=174) encompassing G2019S L2PD patients (n=37), non-manifesting LRRK2 mutation carriers of G2019S, here, G2019S L2NMCs (n=27), R1441G L2PD patients (n=14), R1441G L2NMCs (n=11), iPD (n=40), and controls (n=45). We identified 207 differential proteins in G2019S L2PD compared to controls (39 up/ 168 down) and 67 in G2019S L2NMCs (10 up/ 57 down). G2019S down-regulated proteins affected the endolysosomal pathway, proteostasis and mitochondria, e.g., ATIC, RAB9A, or LAMP1. At the phospho-proteome level, we observed increases in endogenous phosphorylation levels of pSer106 RAB12 in G2019S carriers, which were validated by immunoblotting after 1 year of follow-up (n=48). Freshly collected PBMCs from 3 G2019S L2PD, 1 R1441G L2PD, 1 iPD, and 5 controls (n=10) showed strong diminishment of pSer106 RAB12 phosphorylation levels after in-vitro administration of the MLi-2 LRRK2 inhibitor. Using machine learning, we identified an 18-feature G2019S phospho-/protein signature capable of discriminating G2019S L2PD, L2NMCs, and controls with 96% accuracy that correlated with disease severity, i.e., UPDRS-III motor scoring. Our study identified pSer106 RAB12 as an endogenous biomarker in easily accessible PBMCs from G2019S carriers and suggests that phospho-/proteomic findings in human PBMCs such as pSer106 RAB12 can be deployed as a universal pharmaco-dynamic readout for L2PD, L2NMCs, and iPD. Future work may determine whether pSer106 RAB12 could help with patient enrichment and monitoring drug efficacy in LRRK2 clinical trials.

show abstract

“…Surprisingly, cells with the c mutation in the gene encoding LRRK2 kinase showed no significant differences in the studied parameters, although it is believed that this protein is also associated with autophagy and mitochondrial function [48,49].…”

Section: Discussionmentioning

confidence: 89%

Impaired Mitochondrial Network Morphology and Reactive Oxygen Species Production in Fibroblasts from Parkinson’s Disease Patients

Kritskaya,

Fedotova,

Berezhnov

2024

Biomedicines

View full text Add to dashboard Cite

The mitochondrial network (MN) is a dynamic structure undergoing constant remodeling in the cell. It is assumed that perturbations to the MN may be associated with various pathologies, including Parkinson’s disease (PD). Using automatic image analysis and super-resolution microscopy, we have assessed the MN parameters in fibroblasts from patients with established hereditary PD mutations (associated with PINK1, LRRK2, and α-synuclein, as well as PINK1 and Parkin proteins simultaneously) under normal conditions and after hydrogen peroxide-induced stress. Fibroblasts with the Pink1/Parkin mutation are most different in morphology to fibroblasts obtained from conditionally healthy donors: the MN is larger, and it contains longer mitochondria and accumulated individual mitochondria. In addition to MN, we evaluated other cellular parameters, such as cytosolic and mitochondrial ROS production and mitochondrial membrane potential. It has been shown that mitochondria of fibroblasts with mutations in genes encoding PINK1, α-synuclein, and Pink/Parkin tend towards hyperpolarization and cytosolic ROS overproduction, while mitochondrial ROS production was higher only in fibroblasts with PINK1 and α-synuclein mutations.

show abstract

Regulators of proteostasis are translationally repressed in fibroblasts from patients with sporadic and LRRK2-G2019S Parkinson’s disease

Cited by 9 publications

References 69 publications

Early-stage idiopathic Parkinson’s disease is associated with reduced circular RNA expression

Early-stage idiopathic Parkinson’s disease is associated with reduced circular RNA expression

In-depth mass-spectrometry reveals phospho-RAB12 as a blood biomarker of G2019S LRRK2-driven Parkinson’s

Impaired Mitochondrial Network Morphology and Reactive Oxygen Species Production in Fibroblasts from Parkinson’s Disease Patients

Contact Info

Product

Resources

About