Amyotrophic lateral sclerosis

A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing. By re-analyzing RNA-sequencing datasets from human FTD/ALS brains, we discovered dozens of novel cryptic splicing events in important neuronal genes. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wi

Adenosine Deaminases Acting on RNA (ADAR) enzymes catalyse the conversion of adenosine (A) to inosine (I) within double-stranded RNA (dsRNA) molecules. This mechanism, known as A-I RNA editing, is able to modulate gene expression, RNA stability and protein function.Recently, new therapeutic approaches based on site-directed RNA editing (SDRE) leverage the recoding ability of ADAR to correct pathogenic G to A nucleotide mutations. SDRE allows for the manipulation of genetic information without causing damage to the genome. G-to-A point mutations make up nearly 30% of the pathogenic single nucle

…pathogenic process that characterizes amyotrophic lateral sclerosis (ALS), which is a fatal neurodegenerative disease of motor neurons (MN) in the primary motor cortex and spinal cord. Patients’ death occurs in 3–5 years after the diagnosis due to the progressive palsy and dysfunction of the respiratory system. The etiology is known in most of the patients with the most frequent sporadic ALS (90%), and clinical onset and symptoms are highly heterogeneous. Irrespective of the cause and initial onset the ALS is an almost select

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurological disorder characterized by the gradual degeneration of cells in the spinal cord, brainstem, and motor cortex, leading to manifestations such as weakness, muscle atrophy, and spasticity (Elisen, 2009). A comprehensive understanding of the disease process is currently lacking, making preclinical ALS models crucial to study the mechanisms of pathology insurgence, characterize the disease and test therapeutics approaches. Pathological in vitro models emerged as viable alternative to in vivo studies, consolidating a non-invasive appro

Amyotrophic lateral sclerosis (ALS) is a multisystemic neurodegenerative disease primarily affecting the motor system. Up to 50 % of patients may experience at least subtle cognitive impairment. The current study aimed to investigate the relationship between respiratory insufficiency and cognitive impairment in ALS patients. Cognitive assessment, clinical and demographic information were retrieved for 75 patients with ALS from the medical records of the Institute of Clinical Neurophysiology, University Medical Centre Ljubljana. All patients underwent clinical examination, including respiratory

…Amyotrophic lateral sclerosis (ALS) is a fetal neurodegenerative disease a

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are fatal neurodegenerative disorders with significant clinical and molecular overlaps. Critical events in their pathogenesis involve cytoplasmic mislocalization and loss of nuclear functions of TAR DNA-binding protein 43 (TDP-43). Notably, unconventional metabolic conditions like type 2 diabetes mellitus and dyslipidemia paradoxically correlate with a better prognosis in ALS and FTLD, hinting at potential metabolic pathways in TDP-43-associated neurodegeneration. To better understand the interplay between TDP-43

Aging and neurodegenerative diseases, such as Alzheimer's (AD) or Amyotrophic Lateral Sclerosis (ALS), led to widespread degeneration of long-range connections in cortical structural connectivity (SC). These damages manifest as losses in connections or demyelination of axons. When the SC of the brain is damaged, the functional connectivity (FC, i.e. the dynamic interactions and information exchange between distinct brain regions) is locally and globally perturbed. Despite the close correlation between SC and FC, they are not identical; FC exhibits greater flexibility and can reorganize in resp

Multiple studies suggest that inhibitory neurons are involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS and FTD are two devastating, frequently co-occurring neurodegenerative disorders. While ALS primarily affects motor neurons, causing rapid progressive paralysis and premature death, FTD affects frontal and temporal lobes, leading to severe changes in personality, behaviour, or language skills. To characterise the contribution of inhibitory neurons to these phenotypes, we generated a mouse model based on the expression of mutant Fused in Sarcoma (FUS) selec

…such as spinal cord injuries or amyotrophic lateral sclerosis, cause dysfunction and degeneration of motor neurons leading to severe and untreatable pathological conditions. We aim to explore t

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease that causes the degeneration of motor neurons in the motor cortex and spinal cord. Patients with ALS experience muscle weakness and atrophy in the limbs which eventually leads to paralysis and death. NAD+ is critical for energy metabolism, such as glycolysis and oxidative phosphorylation, but is also involved in non-metabolic cellular reactions. In the current study, we determined whether the supplementation of nicotinamide mononucleotide (NMN), an NAD+ precursor, in the diet had beneficial impacts on disease progr

Background: Amyotrophic lateral sclerosis (ALS) is an intractable neurodegenerative disease of the central nervous system. Despite an unknown etiology, its pathophysiology is considered to be heterogeneous. Recent reports have highlighted the presence of disease-associated microglia (DAM) in the lesions of various neurodegenerative diseases, including that in ALS model animals. However, limited information is available regarding DAM in sporadic cases of ALS in humans.Methods: This study analyzed data from 30 patients with ALS. Autopsy samples of cervical and lumbar lesions obtained from each p

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a selective loss of motor neurons (MN). During ALS, ATP released by neurons and glial cells modulates the neuroglial interplay via activation of P2X receptors. Among these, P2X4 receptor, which is a non-selective cationic channel, has been recently involved in ALS pathogenesis. We found that both the absence of P2X4 or the increase of surface P2X4 using P2X4KO or non-internalized P2X4KI mice respectively, have a beneficial outcome in the SOD1 mice. This paradoxical output suggests a complex cell-role of P2X4 in

…glial activation in a mouse model of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). In particular, we aim to study the role of altered lipid metabolism and neuroinflammation in response to short (12 weeks) and prolonged (14-16 months) high-fat diet (H

…To investigate their role in Amyotrophic lateral sclerosis (ALS) pathogenesis, we depleted PVMs at the presymptomatic stage in our ALS animal model and examined the effects on disease progression and neuroinflammation.In SOD1(G93A) mutated rats, PVM depletion was achieved via clodronate-loaded liposome int

Our research delves into the genetic underpinnings of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), with a specific focus on the prevalent C9orf72 gene mutation. This mutation involves the expansion of a hexanucleotide repeat sequence - GGGGCC - transcribed in both sense (G4C2)n and antisense (C4G2)n directions, leading to the formation of nuclear RNA foci. A pivotal finding in our recent study is the discovery of an interaction between antisense C4G2 repeat RNA and phenylalanine-tRNA synthetase (FARS), resulting in diminished charging of phenylalanine-tRNA and consequ

Amyotrophic lateral sclerosis (ALS) is an incurable disease of the motoric nervous system characterized by loss of function and degeneration of upper and lower motoneurons. Models resembling clinics are required to study pathomechanisms and validate therapeutic options in ALS. Here, we reprogrammed fibroblasts from ALS patient carrying a mutation in Fused in Sarcoma (FUS) gene into induced pluripotent stem cells (iPSCs). An isogenic iPSC line was generated to serve as a control. Doxycycline-inducible NIL-cassette was introduced for motoneuron differentiation. Motoneurons were analyzed for

Amyotrophic Lateral Sclerosis (ALS), is a neurodegenerative disorder characterised by the progressive and rapid loss of upper and lower motor neurons within the central nervous system. ALS exhibits significant heterogeneity, demonstrating variability in clinical presentation, disease progression, and the neural populations affected. This diversity has historically complicated identifying disease mechanisms and devising universally effective treatments. Organoids derived from patient pluripotent stem cells offer an innovative platform to investigate ALS, by recapitulating the multicellular comp

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that lacks effective therapeutic strategies to date. GemPharmatech (GPT) generated the GPT hSOD1 G93A transgenic mouse strain to recapitulate ALS-like phenotypes in an animal model, in support of medical research and drug development. The hSOD1 G93A mouse model carries the G93A mutation in human SOD1 gene, which is widely expressed in mice. We observed an apparent body weight decrease in 25-week-old mice. We further performed a range of behavioral tests to identify the disease onset timing in GPT hSOD1 G93A mouse model,

Intricate and extended mechanisms are in place to allow for repair following injuries of the peripheral nervous system (PNS), particularly at the neuromuscular junction (NMJ). Type 1 endocannabinoid receptors (CB1R) may be involved in the repair process owing to their presence in the PNS and at the NMJ and given their role in axonal growth and neuronal plasticity. Owing to the role of perisynaptic Schwann cells, glial cells at the NMJ, in the regulation of NMJ repair following injury, we postulate that CB1R participate in NMJ denervation and reinnervation processes and that this regulation may

A key challenge in the study of amyotrophic lateral sclerosis (ALS) is that the affected cells, mainly motor neurons (MNs) and muscle cells (MCs), are difficult to isolate and work with in vitro. In this study, we aimed to investigate the pathological features of ALS using cultured dermal fibroblasts, whose isolation requires a minimally invasive biopsy. [SG1] Morphological and biochemical analyses revealed pronounced cytoplasmic buildup and aggregation of TAR DNA-binding protein 43 (TDP-43) in fibroblasts from ALS patients, reflecting alterations commonly observed in MNs. Moreover, transferri

…In neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), it is mislocalized and becomes a central component of cytoplasmic protein aggregates. Our aim was to investigate the interactome of wild-type TDP-43 and TDP-43 without nuclear localization signal (dNLS), which mimics a pathological condition in ALS. We generated inducible mammalian cell lines expressing TDP-43wt and TDP-TDP-43dNLS. Using the BioID method, we investigated the interactome of these

The restrictive element-1 silencing transcription factor (REST) is a transcriptional repressor which acts via epigenetic remodeling to silence numerous target genes. Emerging evidence indicates that REST is a master regulator of neuron-specific genes, not only in neurogenesis and neuronal differentiation, but also in differentiated neurons during postnatal brain development, where it plays a role in fine-tuning of genes involved in synaptic plasticity, and in normal aging, where it promotes neuroprotection by repressing genes involved in oxidative stress and dementia. However, un aberrant REST

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, defined by motor neuron loss, muscle paralysis, and death. ALS individuals often present alterations in cardiovascular function that may evolve into heart failure and death. Mitochondrial dysfunction and oxidative stress are key players in ALS pathophysiology. Thus, improving mitochondrial function and/or antioxidant capacity constitute promising therapeutic strategies to delay ALS progression. We hypothesized that mitochondria-targeted antioxidant AntiOxCIN4 can reduce cardiac oxidative/nitrosative stress in SOD1G93A ALS mice