Targeted long-read sequencing to quantify methylation of the C9orf72 repeat expansion.

Background: The gene C9orf72 harbors a non-coding hexanucleotide repeat expansion known to cause amyotrophic lateral sclerosis and frontotemporal dementia. While previous studies have estimated the length of this repeat expansion in multiple tissues, technological limitations have impeded researchers from exploring additional features, such as methylation levels.

Methods: We aimed to characterize C9orf72 repeat expansions using a targeted, amplification-free long-read sequencing method.

CHMP2B promotes CHMP7 mediated nuclear pore complex injury in sporadic ALS.

Alterations to the composition and function of neuronal nuclear pore complexes (NPCs) have been documented in multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). Moreover, recent work has suggested that injury to the NPC can at least in part contribute to TDP-43 loss of function and mislocalization, a pathological hallmark of ALS and related neurodegenerative diseases. Collectively, these studies highlight a role for disruptions in NPC homeostasis and surveillance as a significant pathophysiologic event in neurodegeneration.

C21ORF2 mutations point towards primary cilia dysfunction in amyotrophic lateral sclerosis.

Progressive loss of motor neurons is the hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain incompletely understood. In this study, we investigate the effects of C21ORF2 mutations, a gene recently linked to ALS, and find that primary cilia are dysfunctional. Human patient-derived mutant C21ORF2 motor neurons have a reduced ciliary frequency and length.

Statistical examination of shared loci in neuropsychiatric diseases using genome-wide association study summary statistics.

Continued methodological advances have enabled numerous statistical approaches for the analysis of summary statistics from genome-wide association studies. Genetic correlation analysis within specific regions enables a new strategy for identifying pleiotropy. Genomic regions with significant 'local' genetic correlations can be investigated further using state-of-the-art methodologies for statistical fine-mapping and variant colocalisation.

Decoding Neurodegeneration: A Review of Molecular Mechanisms and Therapeutic Advances in Alzheimer's, Parkinson's, and ALS.

Neurodegenerative diseases, such as Alzheimer's, Parkinson's, ALS, and Huntington's, remain formidable challenges in medicine, with their relentless progression and limited therapeutic options. These diseases arise from a web of molecular disturbances-misfolded proteins, chronic neuroinflammation, mitochondrial dysfunction, and genetic mutations-that slowly dismantle neuronal integrity. Yet, recent scientific breakthroughs are opening new paths to intervene in these once-intractable conditions.

Magnesium (Mg) and Neurodegeneration: A Comprehensive Overview of Studies on Mg Levels in Biological Specimens in Humans Affected Some Neurodegenerative Disorders with an Update on Therapy and Clinical Trials Supplemented with Selected Animal Studies.

Neurodegenerative diseases, characterized by neuron loss, are a group of neurological disorders that adversely affect the lives of millions of people worldwide. Although several medicines have been approved for managing neurodegenerative diseases, new therapies allowing for a significant slowdown in the progression of neurodegenerative syndromes are constantly being sought. Magnesium (Mg), a crucial mineral necessary for the functioning of organisms, is important to normal central nervous system (CNS) activity.

Semantic behavioral variant frontotemporal dementia and semantic dementia associated with mutations.

Frontotemporal dementia (FTD) is a highly heritable group of neurodegenerative disorders, characterized by varying clinical and pathological features. gene has been described worldwide within the FTD/ALS spectrum but its association with right and left temporal variant of FTD (tvFTD) is still unclear. This study aimed to reclassify a Sardinian FTD cohort according to proposed criteria for the semantic behavioral variant FTD (sbvFTD), explore mutations' association with tvFTD, and review related literature.

Mendelian randomization study of causal link from Cerebrospinal fluid metabolomics to neurodegenerative diseases.

To investigate the causal relationships between cerebrospinal fluid (CSF) metabolites and various neurodegenerative diseases (NDDs), we conducted a two-sample Mendelian randomization (MR) analysis. This study utilized summary statistics from genome-wide association studies (GWAS) of CSF metabolites and four common neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). MR methods were employed to determine causal associations, with the inverse variance weighted method as the primary approach.

RuvBL1/2 reduce toxic dipeptide repeat protein burden in multiple models of C9orf72-ALS/FTD.

A G4C2 hexanucleotide repeat expansion in is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Bidirectional transcription and subsequent repeat-associated non-AUG (RAN) translation of sense and antisense transcripts leads to the formation of five dipeptide repeat (DPR) proteins. These DPRs are toxic in a wide range of cell and animal models.

Impairments of inhibitory neurons in amyotrophic lateral sclerosis and frontotemporal dementia.

Amyotrophic lateral sclerosis and frontotemporal dementia are two fatal neurodegenerative disorders. They are part of a pathophysiological continuum, displaying clinical, neuropathological, and genetic overlaps. There is compelling evidence that neuronal circuit dysfunction is an early feature of both diseases.

Studying C9orf72 dipeptide repeat polypeptide aggregation using an analytical ultracentrifuge equipped with fluorescence detection.

Sedimentation velocity, using an analytical ultracentrifuge equipped with fluorescence detection, and electrophoresis methods are used to study aggregation of proteins in transgenic animal model systems. Our previous work validated the power of this approach in an analysis of mutant huntingtin aggregation. We demonstrate that this method can be applied to another neurodegenerative disease studying the aggregation of three dipeptide repeats (DPRs) produced by aberrant translation of mutant c9orf72 containing large GC hexanucleotide repeats.

Optimizing TDP-43 silencing with siRNA-loaded polymeric nanovectors in neuronal cells for therapeutic applications: balancing knockdown and function.

TAR DNA-binding protein 43 (TDP-43) is a ubiquitously expressed DNA/RNA binding protein critical for regulating gene expression, including transcription, splicing, mRNA stability, and protein translation. Aggregation of pathological TDP-43 proteins in the cytoplasm of neurons and glial cells appears to be a common feature of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases such as frontotemporal dementia (FTD), contributing to motor neuron degeneration and clinical symptoms. Downregulation of TDP-43 expression to prevent or reduce the formation of pathological aggregates is a potential therapeutic approach for treating TDP-43-related diseases.