Faculty Opinions recommendation of Genome-Scale Networks Link Neurodegenerative Disease Genes to α-Synuclein through Specific Molecular Pathways.

2017 ◽  
Author(s):  
Joseph Jankovic
Keyword(s):  
Neurodegenerative Disease ◽  
Disease Genes ◽  
Molecular Pathways ◽  
Genome Scale

scholarly journals Genome-Scale Networks Link Neurodegenerative Disease Genes to α-Synuclein through Specific Molecular Pathways

Cell Systems ◽  
2017 ◽  
Vol 4 (2) ◽  
pp. 157-170.e14 ◽  
Author(s):  
Vikram Khurana ◽  
Jian Peng ◽  
Chee Yeun Chung ◽  
Pavan K. Auluck ◽  
Saranna Fanning ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Disease Genes ◽  
Molecular Pathways ◽  
Genome Scale

scholarly journals Author Correction: Mendelian neurodegenerative disease genes involved in autophagy

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Eleanna Stamatakou ◽  
Lidia Wrobel ◽  
Sandra Malmgren Hill ◽  
Claudia Puri ◽  
Sung Min Son ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Disease Genes

scholarly journals Targeted DNA methylation of neurodegenerative disease genes via homology directed repair

2019 ◽  
Author(s):  
Christopher P Cali ◽  
Daniel S Park ◽  
Edward B Lee
Keyword(s):  
Dna Methylation ◽  
Neurodegenerative Disease ◽  
Cellular Response ◽  
Regulatory Region ◽  
Strand Break ◽  
Dna Methyltransferases ◽  
Disease Genes ◽  
Fusion Construct ◽  
Homology Directed Repair

Abstract DNA methyltransferases (DNMTs) are thought to be involved in the cellular response to DNA damage, thus linking DNA repair mechanisms with DNA methylation. In this study we present Homology Assisted Repair Dependent Epigenetic eNgineering (HARDEN), a novel method of targeted DNA methylation that utilizes endogenous DNA double strand break repair pathways. This method allows for stable targeted DNA methylation through the process of homology directed repair (HDR) via an in vitro methylated exogenous repair template. We demonstrate that HARDEN can be applied to the neurodegenerative disease genes C9orf72 and APP, and methylation can be induced via HDR with both single and double stranded methylated repair templates. HARDEN allows for higher targeted DNA methylation levels than a dCas9-DNMT3a fusion protein construct at C9orf72, and genome-wide methylation analysis reveals no significant off-target methylation changes when inducing methylation via HARDEN, whereas the dCas9-DNMT3a fusion construct causes global off-target methylation. HARDEN is applied to generate a patient derived iPSC model of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) that recapitulates DNA methylation patterns seen in patients, demonstrating that DNA methylation of the 5′ regulatory region directly reduces C9orf72 expression and increases histone H3K9 tri-methylation levels.

scholarly journals Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders

2018 ◽  
Vol 4 (1) ◽  
pp. e212 ◽  
Author(s):  
Gloria T. Haskell ◽  
Michael C. Adams ◽  
Zheng Fan ◽  
Krunal Amin ◽  
Roberto J. Guzman Badillo ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Molecular Diagnosis ◽  
Diagnostic Yield ◽  
Neuromuscular Disorders ◽  
Gene List ◽  
Disease Genes ◽  
Causative Gene ◽  
Pathogenic Variants ◽  
Prior Testing ◽  
Genome Scale

ObjectiveTo evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs).MethodsWe performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup.ResultsThe overall diagnostic yield of exome sequencing in our cohort was 12.9%, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. Targeted gene lists had the same diagnostic yield as a broad NMD gene list in patients with clear neuropathy or myopathy phenotypes, but evaluation of a broader set of disease genes was needed for patients with complex NMD phenotypes. Most patients with NMD had undergone prior testing, but only 10/16 (63%) of these procedures, such as muscle biopsy, were informative in pointing to a final molecular diagnosis.ConclusionsGenome-scale sequencing or analysis of a panel of relevant genes used early in the evaluation of patients with NMDs can provide or clarify a diagnosis and minimize invasive testing in many cases.

scholarly journals Detecting new neurodegenerative disease genes: does phenotype accuracy limit the horizon?

2009 ◽  
Vol 25 (11) ◽  
pp. 486-488 ◽  
Author(s):  
David C. Samuels ◽  
David J. Burn ◽  
Patrick F. Chinnery
Keyword(s):  
Neurodegenerative Disease ◽  
Disease Genes

scholarly journals Using Mendelian randomization to understand and develop treatments for neurodegenerative disease

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Catherine S Storm ◽  
Demis A Kia ◽  
Mona Almramhi ◽  
Nicholas W Wood
Keyword(s):  
Risk Factors ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Translational Medicine ◽  
Mendelian Randomization ◽  
Genetic Data ◽  
Molecular Pathways ◽  
Disease Research ◽  
The Impact

Abstract Common neurodegenerative diseases are thought to arise from a combination of environmental and genetic exposures. Mendelian randomization is a powerful way to leverage existing genetic data to investigate causal relationships between risk factors and disease. In recent years, Mendelian randomization has gathered considerable traction in neurodegenerative disease research, providing valuable insights into the aetiology of these conditions. This review aims to evaluate the impact of Mendelian randomization studies on translational medicine for neurodegenerative diseases, highlighting the advances made and challenges faced. We will first describe the fundamental principles and limitations of Mendelian randomization and then discuss the lessons from Mendelian randomization studies of environmental risk factors for neurodegeneration. We will illustrate how Mendelian randomization projects have used novel resources to study molecular pathways of neurodegenerative disease and discuss the emerging role of Mendelian randomization in drug development. Finally, we will conclude with our view of the future of Mendelian randomization in these conditions, underscoring unanswered questions in this field.

scholarly journals Mendelian neurodegenerative disease genes involved in autophagy

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Eleanna Stamatakou ◽  
Lidia Wróbel ◽  
Sandra Malmgren Hill ◽  
Claudia Puri ◽  
Sung Min Son ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Disease Genes

scholarly journals Controllability of molecular pathways

2019 ◽  
Author(s):  
Stefan Wuchty
Keyword(s):  
Molecular Interaction ◽  
Drug Targets ◽  
Interaction Networks ◽  
Disease Genes ◽  
Molecular Pathways ◽  
Control Analysis ◽  
Cellular Activity ◽  
Functional Characteristics ◽  
Molecular Interaction Networks ◽  
Evolutionarily Conserved

ABSTRACTInputs to molecular pathways that are the backbone of cellular activity drive the cell to certain outcomes and phenotypes. Here, we investigated proteins that topologically controlled different human pathways represented as independent molecular interaction networks, suggesting that a minority of proteins control a high number of pathways and vice versa. Transcending different topological levels, proteins that controlled a large number of pathways also controlled a network of interactions when all pathways were combined. Furthermore, control proteins that were robust when interactions were rewired or inverted also increasingly controlled an increasing number of pathways. As for functional characteristics, such control proteins were enriched with regulatory and signaling genes, disease genes and drug targets. Focusing on evolutionary characteristics, proteins that controlled different pathways had a penchant to be evolutionarily conserved as equal counterparts in other organisms, indicating the fundamental role that control analysis of pathways plays for our understanding of regulation, disease and evolution.

POPDC proteins and cardiac function

2019 ◽  
Vol 47 (5) ◽  
pp. 1393-1404 ◽  
Author(s):  
Thomas Brand
Keyword(s):  
Potential Role ◽  
Striated Muscle ◽  
Short Review ◽  
Effector Proteins ◽  
Muscle Disease ◽  
Disease Genes ◽  
Protein Protein Interaction ◽  
Interaction Partners ◽  
And Function

Abstract The Popeye domain-containing gene family encodes a novel class of cAMP effector proteins in striated muscle tissue. In this short review, we first introduce the protein family and discuss their structure and function with an emphasis on their role in cyclic AMP signalling. Another focus of this review is the recently discovered role of POPDC genes as striated muscle disease genes, which have been associated with cardiac arrhythmia and muscular dystrophy. The pathological phenotypes observed in patients will be compared with phenotypes present in null and knockin mutations in zebrafish and mouse. A number of protein–protein interaction partners have been discovered and the potential role of POPDC proteins to control the subcellular localization and function of these interacting proteins will be discussed. Finally, we outline several areas, where research is urgently needed.

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