Studying Rare Movement Disorders: From Whole-Exome Sequencing to New Diagnostic and Therapeutic Approaches in a Modern Genetic Clinic DOI Creative Commons
Luca Marsili, Kevin R. Duque, Jesus Abanto

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(12), P. 2673 - 2673

Published: Nov. 23, 2024

Background: Rare movement disorders often have a genetic etiology. New technological advances increased the odds of achieving diagnoses: next-generation sequencing (NGS) (whole-exome sequencing—WES; whole-genome sequencing—WGS) and long-read (LRS). In 2017, we launched WES program for patients with rare suspected We aim to describe accumulated experience modern disorder clinic, highlighting how different available tests might be prioritized according clinical phenotype pattern inheritance. Methods: Participants were studied through analysis. Descriptive statistics, including mean, standard deviation, counts, percentages, used summarize demographic characteristics in all subjects each type result [pathogenic or likely pathogenic, variants uncertain significance (VUS), negative]. Results: 88 (93.2% Caucasian, 5.72% African American, 1.08% Hispanic Latino). After excluding six family members from four index participants, diagnostic yield reached 27% (22/82 probands). The age at onset was significantly lower pathogenic/likely pathogenic variants. most common phenotypes ataxia parkinsonism. Dystonia, ataxia, leukoencephalopathy, parkinsonism associated diagnoses. Conclusions: propose comprehensive protocol decision tree testing WGS LRS, return results, re-analysis inconclusive data increase neurogenetic disorders.

Language: Английский

A blood-based marker of mitochondrial DNA damage in Parkinson’s disease DOI Open Access
Rui Qi, Esther Sammler, Claudia P. González-Hunt

et al.

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(711)

Published: Aug. 30, 2023

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on basis of shared etiology are required to ensure success therapies in clinical trials. Mitochondrial dysfunction plays a prominent role pathogenesis PD. Previously, we found brain region–specific accumulation mitochondrial DNA (mtDNA) damage PD neuronal culture animal models, as well human postmortem tissue. To investigate mtDNA potential blood-based marker for PD, describe herein PCR-based assay (Mito DX ) that allows accurate real-time quantification scalable platform. We was increased peripheral blood mononuclear cells derived from with idiopathic those harboring PD-associated leucine-rich repeat kinase 2 ( LRRK2 G2019S mutation comparison age-matched controls. In addition, elevated non–disease-manifesting carriers, demonstrating can occur irrespective diagnosis. further established Lrrk2 knock-in mice displayed damage, whereas knockout showed fewer lesions ventral midbrain, compared wild-type control mice. Furthermore, small-molecule inhibitor mitigated rotenone rat midbrain neuron model patient–derived lymphoblastoid cell lines. Quantifying using Mito may have utility candidate measuring pharmacodynamic response inhibitors.

Language: Английский

Citations

42
LONG-RANGE PCR AS A TOOL FOR EVALUATING MITOCHONDRIAL DNA DAMAGE: PRINCIPLES, BENEFITS, AND LIMITATIONS OF THE TECHNIQUE DOI
Artem P. Gureev, Veronika V. Nesterova, Irina S. Sadovnikova

et al.

DNA repair, Journal Year: 2025, Volume and Issue: 146, P. 103812 - 103812

Published: Jan. 18, 2025

Language: Английский

Citations

1
Parkinson’s Disease: The Neurodegenerative Enigma Under the “Undercurrent” of Endoplasmic Reticulum Stress DOI Open Access
Xiangrui Kong, Tingting Liu, Jianshe Wei

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 3367 - 3367

Published: April 3, 2025

Parkinson's disease (PD), a prevalent neurodegenerative disorder, demonstrates the critical involvement of endoplasmic reticulum stress (ERS) in its pathogenesis. This review comprehensively examines role and molecular mechanisms ERS PD. represents cellular response triggered by imbalances (ER) homeostasis, induced factors such as hypoxia misfolded protein aggregation, which activate unfolded (UPR) through inositol-requiring enzyme 1 (IRE1), kinase R-like (PERK), activating transcription factor 6 (ATF6) pathways. Clinical, animal model, studies have consistently demonstrated strong association between PD ERS. Abnormal expression ERS-related molecules patients' brains cerebrospinal fluid (CSF) correlates with progression. In models (e.g., Drosophila mice), inhibition alleviates dopaminergic neuronal damage. Cellular experiments reveal that PD-mimicking pathological conditions induce ERS, while interactions mitochondrial dysfunction promote apoptosis. Mechanistically, (1) aggregation α-synuclein (α-syn) mutually reinforce neuron damage; (2) leucine-rich repeat 2 (LRRK2) gene mutations thrombospondin-1 (THBS1)/transforming growth beta (TGF-β1) interactions; (3) Parkin PTEN-induced (PINK1) regulate Furthermore, interacts dysfunction, oxidative stress, neuroinflammation to exacerbate injury. Emerging therapeutic strategies show significant potential, including artificial intelligence (AI)-assisted drug design targeting pathways precision medicine approaches exploring non-pharmacological interventions personalized electroacupuncture. Future research should focus on elucidating identifying novel targets develop more effective treatments for patients, ultimately improving their quality life.

Language: Английский

Citations

0
Inactive S. aureus Cas9 downregulates alpha-synuclein and reduces mtDNA damage and oxidative stress levels in human stem cell model of Parkinson’s disease DOI Creative Commons
Danuta Sastre, Faria Zafar, C. Alejandra Morato Torres

et al.

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Oct. 18, 2023

Parkinson's disease (PD) is one of the most common neurodegenerative diseases, but no modifying therapies have been successful in clinical translation presenting a major unmet medical need. A promising target alpha-synuclein or its aggregated form, which accumulates brain PD patients as Lewy bodies. While it not entirely clear protein species relevant, mere overexpression hereditary forms leads to neurodegeneration. To specifically address gene regulation alpha-synuclein, we developed CRISPR interference (CRISPRi) system based on nuclease dead S. aureus Cas9 (SadCas9) fused with transcriptional repressor domain Krueppel-associated box controllably repress expression at level. We screened single guide (sg)RNAs across SNCA promoter and identified several sgRNAs that mediate downregulation varying levels. CRISPRi iPSC-derived neuronal cultures from patient an genomic triplication showed functional recovery by reduction oxidative stress mitochondrial DNA damage. Our results are proof-of-concept vitro for precision medicine targeting promoter. The approach presents new model understand safe levels novel therapeutic strategy related alpha-synucleinopathies.

Language: Английский

Citations

7
Nuclease-dead S.aureusCas9 downregulates alpha-synuclein and reduces mtDNA damage and oxidative stress levels in patient-derived stem cell model of Parkinson’s disease DOI Creative Commons
Danuta Sastre, Faria Zafar, C. Alejandra Morato Torres

et al.

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

Published: Jan. 24, 2023

Parkinson's disease (PD) is one of the most common neurodegenerative diseases, but no modifying therapies have been successful in clinical translation presenting a major unmet medical need. A promising target alpha-synuclein or its aggregated form, which accumulates brain PD patients as Lewy bodies. While it not entirely clear protein species relevant, mere overexpression hereditary forms leads to neurodegeneration. To specifically address gene regulation alpha-synuclein, we developed CRISPR interference (CRISPRi) system based on nuclease dead

Language: Английский

Citations

4
Selective dopaminergic neurotoxicity modulated by inherent cell-type specific neurobiology DOI
Fatema Currim,

Reeya Tanwar,

Josephine M. Brown-Leung

et al.

NeuroToxicology, Journal Year: 2024, Volume and Issue: 103, P. 266 - 287

Published: July 1, 2024

Language: Английский

Citations

1
Single-cell transcriptomic changes in oligodendrocytes and precursors derived from Parkinson's disease patient-iPSCs with LRRK2-G2019S mutation DOI Creative Commons

Mohammad Dehestani,

Wiebke Kessler,

Nasser Karmali

et al.

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

Published: July 3, 2024

Abstract Despite extensive research, the contribution of LRRK2 p.G2019S mutation to Parkinson’s disease (PD) remains unclear. Recent findings indicate oligodendrocytes (ODCs) and their progenitors are vulnerable in PD pathogenesis. Notably, oligodendrocyte precursor cells (OPCs) exhibit high endogenous expression . We induced patient-iPSCs with into oligodendroglial lineages performed single-cell RNA sequencing. Cell type composition analysis revealed an increase OPCs, proliferating OPCs ciliated ependymal lines, all which characterized by expression. Differential transcriptomic changes several pathways, including down-regulation genes related myelin assembly ODCs, semaphorin-plexin pathway cilium movement OPCs. Cell-cell communication identified significant alterations signaling pathways a deactivation PSAP activation MIF lines. Additionally, we observed overall SEMA6 cell lines; however, derived from these lines specifically lost due SEMA6A PLXNA2 Pseudotemporal trajectory that SHH had significantly altered along pseudotime, accompanied higher levels propose dysfunctional signaling, cilia might represent early events pathology.

Language: Английский

Citations

1
Leucine-rich repeat kinase 2 (LRRK2) inhibitors for Parkinson’s disease: a patent review of the literature to date DOI

Margaux Morez,

Antonio Jesús Lara Ordóñez, Patricia Melnyk

et al.

Expert Opinion on Therapeutic Patents, Journal Year: 2024, Volume and Issue: 34(9), P. 773 - 788

Published: July 18, 2024

Nearly two decades after leucine rich repeat kinase 2 (LRRK2) was discovered as a genetic determinant of Parkinson's disease (PD), LRRK2 has emerged priority therapeutic target in PD and inhibition its activity is hypothesized to be beneficial.

Language: Английский

Citations

1
Studying Rare Movement Disorders: From Whole-Exome Sequencing to New Diagnostic and Therapeutic Approaches in a Modern Genetic Clinic DOI Creative Commons
Luca Marsili, Kevin R. Duque, Jesus Abanto

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(12), P. 2673 - 2673

Published: Nov. 23, 2024

Background: Rare movement disorders often have a genetic etiology. New technological advances increased the odds of achieving diagnoses: next-generation sequencing (NGS) (whole-exome sequencing—WES; whole-genome sequencing—WGS) and long-read (LRS). In 2017, we launched WES program for patients with rare suspected We aim to describe accumulated experience modern disorder clinic, highlighting how different available tests might be prioritized according clinical phenotype pattern inheritance. Methods: Participants were studied through analysis. Descriptive statistics, including mean, standard deviation, counts, percentages, used summarize demographic characteristics in all subjects each type result [pathogenic or likely pathogenic, variants uncertain significance (VUS), negative]. Results: 88 (93.2% Caucasian, 5.72% African American, 1.08% Hispanic Latino). After excluding six family members from four index participants, diagnostic yield reached 27% (22/82 probands). The age at onset was significantly lower pathogenic/likely pathogenic variants. most common phenotypes ataxia parkinsonism. Dystonia, ataxia, leukoencephalopathy, parkinsonism associated diagnoses. Conclusions: propose comprehensive protocol decision tree testing WGS LRS, return results, re-analysis inconclusive data increase neurogenetic disorders.

Language: Английский

Citations

0