Targeting mRNA translation in Parkinson’s disease

Correddu, Danilo; Leung, Ivanhoe K. H.

doi:10.1016/j.drudis.2019.04.003

Cited by 11 publications

(6 citation statements)

References 98 publications

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“…Translation , a process downstream of rRNA processing , has been implicated in PD, as several PD-related proteins have been shown to intervene with this process. For example, LRRK2 (a commonly mutated protein in PD) modulates the amount of eukaryotic initiation factors, disrupting the initial phases of mRNA translation and promoting PD development [19]. The same effect could be achieved through PINK1 mutations, as they influence LRRK2 levels [5].…”

Section: Resultsmentioning

confidence: 99%

MONFIT: Multi-omics factorization-based integration of time-series data sheds light on Parkinson’s disease

Mihajlović,

Malod-Dognin,

Ameli

et al. 2024

Preprint

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Parkinson’s disease (PD) is a severe and complex multifactorial neurodegenerative disease with still elusive pathophysiology preventing the development of curative treatments. Molecular deep phenotyping by longitudinal multi-omics is a promising approach to identify mechanisms of PD aetiology and its progression. However, the heterogeneous data require new analysis frameworks to understand disease progression across biological entities and processes. Here, we present MONFIT, a holistic analysis pipeline that integrates and mines time-series single-cell RNA-sequencing data with bulk proteomics and metabolomics data by non-negative matrix tri-factorization, enabling prior knowledge incorporation from molecular networks. First, MONIFT integrates time-point-specific data and then holistically mines the integrated data across time points. By applying MONFIT to longitudinal multi-omics data of differentiation of PD and control patient-derived induced pluripotent stem cells into dopaminergic neurons, we identify novel PD-associated genes, emphasize molecular pathways that play important roles in PD pathology, and suggest new intervention opportunities using drug-repurposing. MONFIT is fully adaptable to other multi-omics data sets.

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Section: Resultsmentioning

confidence: 99%

MONFIT: Multi-omics factorization-based integration of time-series data sheds light on Parkinson’s disease

Mihajlović,

Malod-Dognin,

Ameli

et al. 2024

Preprint

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“…The D2R mRNA expression significantly reduced in the striatum of PD patients, but the reductions are lesser than seen in the receptor autoradiography studies. A reason for this discrepancy may be that the protein level is not always proportional to the mRNA expression, since protein translation from mRNA may be attenuated in PD brains, 10 but this warrants further investigations. The reduction in D2R expression from this study is similar to Farkas’s study where the binding of [ 3 H]raclopride, which has 11.25 folds preferential binding to D2R than D3R, in PD postmortem putamen is ~ 8% of the control group (PD 3.73 ± 0.07, control 47.97 ± 10.00 fmol/g) 11 .…”

Section: Discussionmentioning

confidence: 99%

Dopamine D1 + D3 receptor density may correlate with parkinson disease clinical features

Yang

Knight

et al. 2020

Ann Clin Transl Neurol

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ObjectiveDopamine D2‐like receptors – mainly dopamine D2 receptors (D2R) and dopamine D3 receptors (D3R) – are believed to be greatly involved in the pathology of Parkinson disease (PD) progression. However, these receptors have not been precisely examined in PD patients. Our aim was to quantitatively calculate the exact densities of dopamine D1 receptors (D1R), D2R, and D3R in control, Alzheimer disease (AD), and Lewy body disease (LBD) patients (including PD, Dementia with Lewy bodies, and Parkinson disease dementia); and analyze the relationship between dopamine receptors and clinical PD manifestations.MethodsWe analyzed the densities of D1R, D2R, and D3R in the striatum and substantia nigra (SN) using a novel quantitative autoradiography procedure previously developed by our group. We also examined the expression of D2R and D3R mRNA in the striatum by in situ hybridization.ResultsThe results showed that although no differences of striatal D1R were found among all groups; D2R was significantly decreased in the striatum of PD patients when compared with control and AD patients. Some clinical manifestations: age of onset, PD stage, dopamine responsiveness, and survival time after onset; showed a better correlation with striatal D1R + D3R densities combined compared to D1R or D3R alone.InterpretationThere is a possibility that we may infer the results in diagnosis, treatment, and prognosis of PD by detecting D1R + D3R as opposed to using dopamine D1 or D3 receptors alone. This is especially true for elderly patients with low D2R expression as is common in this disease.

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“…In addition, some of the known PD-associated proteins are also shown to have RNA or protein translation roles. This link between mRNA translation is poorly understood, but a few reviews have highlighted that restoring translation and proteostasis might be a useful target for new therapeutics ( Correddu and Leung, 2019 ; Zhou et al, 2019 ). Impaired proteostasis at the synapse could also be important for PD ( Nachman and Verstreken, 2022 ) while reduced synaptic activity and dysregulated extracellular matrix pathways have recently been reported in midbrain neurons from PD patients, providing evidence that synaptopathy is a general phenotype in PD ( Stern et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Proteomics analysis of the p.G849D variant in neurexin 2 alpha may reveal insight into Parkinson’s disease pathobiology

Cuttler

Fortuin

Müller-Nedebock

et al. 2022

Front. Aging Neurosci.

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Parkinson’s disease (PD), the fastest-growing neurological disorder globally, has a complex etiology. A previous study by our group identified the p.G849D variant in neurexin 2 (NRXN2), encoding the synaptic protein, NRXN2α, as a possible causal variant of PD. Therefore, we aimed to perform functional studies using proteomics in an attempt to understand the biological pathways affected by the variant. We hypothesized that this may reveal insight into the pathobiology of PD. Wild-type and mutant NRXN2α plasmids were transfected into SH-SY5Y cells. Thereafter, total protein was extracted and prepared for mass spectrometry using a Thermo Scientific Fusion mass spectrometer equipped with a Nanospray Flex ionization source. The data were then interrogated against the UniProt H. sapiens database and afterward, pathway and enrichment analyses were performed using in silico tools. Overexpression of the wild-type protein led to the enrichment of proteins involved in neurodegenerative diseases, while overexpression of the mutant protein led to the decline of proteins involved in ribosomal functioning. Thus, we concluded that the wild-type NRXN2α may be involved in pathways related to the development of neurodegenerative disorders, and that biological processes related to the ribosome, transcription, and tRNA, specifically at the synapse, could be an important mechanism in PD. Future studies targeting translation at the synapse in PD could therefore provide further information on the pathobiology of the disease.

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Targeting mRNA translation in Parkinson’s disease

Cited by 11 publications

References 98 publications

MONFIT: Multi-omics factorization-based integration of time-series data sheds light on Parkinson’s disease

MONFIT: Multi-omics factorization-based integration of time-series data sheds light on Parkinson’s disease

Dopamine D1 + D3 receptor density may correlate with parkinson disease clinical features

Proteomics analysis of the p.G849D variant in neurexin 2 alpha may reveal insight into Parkinson’s disease pathobiology

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