Improving ALS Molecular Diagnosis Through Functional Assays: Reassessment of a Variant of Uncertain Significance.

Genetic testing in amyotrophic lateral sclerosis (ALS) often reveals variants of uncertain significance (VUS), which are frequently omitted from diagnostic reports or reported with limited clinical interpretation. To address this gap, we developed a rapid functional assessment pipeline in collaboration with FILSLAN, the French ALS care network, combining in vitro and in vivo neurogenetic assays. We illustrate this approach through the reclassification of the p.

scFv intrabody targeting wildtype TDP-43 presents protective effects in a cellular model of TDP-43 proteinopathy.

TDP-43 proteinopathies are neurological disorders marked by the abnormal accumulation of TDP-43 in the cytoplasm. This mislocalization disrupts the normal function of the protein. In most cases, it is the wildtype (wt) form of the protein that is involved.

Critical impact of lysine 136 in TDP-43 phase separation, compartmentalization, and aggregation in living vertebrates.

TDP-43 is a nuclear RNA-binding protein that undergoes liquid-liquid phase separation (LLPS) and forms insoluble aggregates in neurodegenerative diseases. By studying TDP-43 in living vertebrates, we confirmed that TDP-43 undergoes LLPS and forms dynamic biomolecular condensates in spinal motor neurons. We validated that interfering with the lysine residue at position 136 altered the phase separation behavior of TDP-43 by reducing cytoplasmic mislocalization and aggregation.

Identification of disease-associated molecular signatures in the Prp-TDP-43A315T mouse model of ALS: Toward preclinical biomarker development.

Identifying disease-related molecular signatures that can be used as biomarkers is critical for the development of preclinical therapies for amyotrophic lateral sclerosis (ALS). In this study, we focused on the Prp-TDP-43A315T transgenic mouse model of ALS to explore peripheral and central molecular alterations associated with disease progression. Prp-TDP-43A315T transgenic (Tg) and C57BL/6J wild-type mice were monitored from 50 to 400 postnatal days.

MAPT mutations in amyotrophic lateral sclerosis: clinical, neuropathological and functional insights.

Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a well-established disease continuum, underpinned by TDP43-pathology. In contrast, the clinical manifestations of Tau-linked disorders are typically limited to cognitive phenotypes or atypical parkinsonism, although few reports describe motor neuron involvement associated with MAPT (microtubule-associated protein Tau) mutations. This study aimed to investigate the contribution of MAPT to the ALS phenotype.

Metabolomic and Proteomic Profiling of Serum-Derived Extracellular Vesicles from Early-Stage Amyotrophic Lateral Sclerosis Patients.

The identification of reliable biomarkers for amyotrophic lateral sclerosis (ALS) is an unmet medical need for the development of diagnostic and therapeutic strategies. Brain-derived extracellular vesicles (EVs) have been described in peripheral blood serum and used as a direct readout of the status of the central nervous system. Here, we aimed to explore exosome-enriched EVs (referred to simply as EVs) from ALS patients via omics analysis at an early disease stage.

Oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling and therapeutic implications.

Background: Despite several studies suggesting a potential oligogenic risk model in amyotrophic lateral sclerosis (ALS), case-control statistical evidence implicating oligogenicity with disease risk or clinical outcomes is limited. Considering its direct clinical and therapeutic implications, we aim to perform a large-scale robust investigation of oligogenicity in ALS risk and in the disease clinical course.

Methods: We leveraged Project MinE genome sequencing datasets (6711 cases and 2391 controls) to identify associations between oligogenicity in known ALS genes and disease risk, as well as clinical outcomes.

Sex-specific DNA methylation differences in Amyotrophic lateral sclerosis.

Sex is an important covariate in all genetic and epigenetic research due to its role in the incidence, progression and outcome of many phenotypic characteristics and human diseases. Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a sex bias towards higher incidence in males. Here, we report for the first time a blood-based epigenome-wide association study meta-analysis in 9274 individuals after stringent quality control (5529 males and 3975 females).

Gut metabolomic and microbiota analyses in ALS mice reveal specific metabolites despite the absence of significant gut dysbiosis.

Objective: Over the past years, interest in the role of gut microbiota in neurodegenerative diseases has emerged. Despite numerous publications over the past decade, both in human and pre-clinical studies, there is no clear consensus on the microbiota's role or involvement in ALS. Few studies on mouse models of ALS highlighted a correlation between specific bacteria species and the prognostic or severity of the disease.

Dynamic Expression of Genes Encoding Ubiquitin Conjugating Enzymes (E2s) During Neuronal Differentiation and Maturation: Implications for Neurodevelopmental Disorders and Neurodegenerative Diseases.

The ubiquitination process plays a crucial role in neuronal differentiation and function. Numerous studies have focused on the expression and functions of E3 ligases during these different stages, far fewer on E2 conjugating enzymes. In mice, as in humans, these E2s belong to 17 conjugating enzyme families.

N-Terminal Fragments of TDP-43-In Vitro Analysis and Implication in the Pathophysiology of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration.

Abnormal cytoplasmic aggregates containing the TDP-43 protein and its fragments are present in the central nervous system of the majority of patients with amyotrophic lateral sclerosis (ALS) and in patients with frontotemporal lobar degeneration (FTLD). Many studies have focused on the C-terminal cleavage products of TDP-43 (CTFs), but few have focused on the N-terminal products (NTFs), yet several works and their protein domain composition support the involvement of NTFs in pathophysiology. In the present study, we expressed six NTFs of TDP-43, normally generated in vivo by proteases or following the presence of pathogenic genetic truncating variants, in HEK-293T cells.

Mutations in the tail and rod domains of the neurofilament heavy-chain gene increase the risk of ALS.

Objective: Neurofilament heavy-chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk.

Pharmacometabolomics applied to low-dose interleukin-2 treatment in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The immunosuppressive functions of regulatory T lymphocytes (Tregs) are impaired in ALS, and correlate to disease progression. The phase 2a IMODALS trial reported an increase in Treg number in ALS patients following the administration of low-dose (ld) interleukin-2 (IL-2).

The effect of pH alterations on TDP-43 in a cellular model of amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. The pathophysiology of ALS is not well understood but TDP-43 proteinopathy (aggregation and mislocalization) is one of the major phenomena described. Several factors can influence TDP-43 behavior such as mild pH alterations that can induce conformational changes in recombinant TDP-43, increasing its propensity to aggregate.

Neutrophil to Lymphocyte Ratio as a Prognostic Marker in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative motor neuron disease and remains misunderstood with a difficult diagnosis and prognosis. The implication of the immune system is recognized in ALS pathophysiology, hence the interest in leucocyte count as lymphocytes and neutrophils. The neutrophil-to-lymphocyte ratio (NLR) has recently been used as a prognosis factor to assess the progression of ALS.

Implication of Central Nervous System Barrier Impairment in Amyotrophic Lateral Sclerosis: Gender-Related Difference in Patients.

Central nervous system (CNS) barrier impairment has been reported in amyotrophic lateral sclerosis (ALS), highlighting its potential significance in the disease. In this context, we aim to shed light on its involvement in the disease, by determining albumin quotient (QAlb) at the time of diagnosis of ALS in a large cohort of patients. Patients from the university hospital of Tours ( = 307) were included in this monocentric, retrospective study.

Contribution of the dihydropyrimidinase-like proteins family in synaptic physiology and in neurodevelopmental disorders.

The dihydropyrimidinase-like (DPYSL) proteins, also designated as the collapsin response mediators (CRMP) proteins, constitute a family of five cytosolic phosphoproteins abundantly expressed in the developing nervous system but down-regulated in the adult mouse brain. The DPYSL proteins were initially identified as effectors of semaphorin 3A (Sema3A) signaling and consequently involved in regulation of growth cone collapse in young developing neurons. To date, it has been established that DPYSL proteins mediate signals for numerous intracellular/extracellular pathways and play major roles in variety of cellular process including cell migration, neurite extension, axonal guidance, dendritic spine development and synaptic plasticity through their phosphorylation status.

Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival.

Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts.

Evaluation of arterial blood gas parameters as prognostic markers in amyotrophic lateral sclerosis.

Background: Forced vital capacity (FVC) remains difficult to determine for some patients suffering from amyotrophic lateral sclerosis (ALS) due to the rapid progression of the disease. Arterial blood gas (ABG) parameters could represent a valuable alternative. The aim of this study was therefore to evaluate the correlation between ABG parameters and FVC, along with the prognostic ability of ABG parameters, in a large cohort of ALS patients.