TopicNeuroscience

amyotrophic lateral sclerosis

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3Seminars

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SeminarNeuroscience

Expanding mechanisms and therapeutic targets for neurodegenerative disease

Aaron D. Gitler

Department of Genetics, Stanford University

Jun 5, 2025

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-wide association studies, but how those variants increase risk for disease is unknown. We discovered that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harboring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function. Recent analyses have revealed even further changes in TDP-43 target genes, including widespread changes in alternative polyadenylation, impacting expression of disease-relevant genes (e.g., ELP1, NEFL, and TMEM106B) and providing evidence that alternative polyadenylation is a new facet of TDP-43 pathology.

SeminarNeuroscience

Zebrafish models help untangle genetic interactions in motor neuron degeneration

Sorana Ciura

Imagine Institute, Université de Paris

May 31, 2022

Due to high homology to the human genome and rapid development, zebrafish have been successfully used to model diseases of the neuromuscular system. In this seminar, I will present current advances in modeling genetic causes of Amyotrophic Lateral Sclerosis (ALS), the most common motor neuron degeneration and show how epistatic interaction studies in zebrafish have helped elucidate synergistic effects of major ALS genes and their cellular targets.

SeminarNeuroscience

Genetic therapies for Huntington’s disease, what does the future hold for neurodegenerative disorders?

Sarah Tabrizi

University College London

Mar 9, 2021

There are no effective disease-modifying therapies for neurodegenerative diseases such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis or Huntington’s disease. Huntington’s disease (HD) is a devastating autosomal dominantly inherited neurodegenerative disease and the world’s most common genetic dementia. I will present an overview of important approaches in development for targeting mutant HTT DNA and RNA (Tabrizi et al Neuron 2019), the cause of HD pathogenesis, and the translational pathway from bench to clinic for a HTT targeting antisense oligonucleotide (Tabrizi et al New England Journal of Medicine 2019, Tabrizi, Science 2020) which is now in phase 3 studies. In my talk I will also review some of the genetic approaches in development for other CNS diseases. I will talk a bit about my journey as a clinician scientist and share some of my learnings for young scientists on how to survive a career in science.

amyotrophic lateral sclerosis

Latest

Expanding mechanisms and therapeutic targets for neurodegenerative disease

Zebrafish models help untangle genetic interactions in motor neuron degeneration

Genetic therapies for Huntington’s disease, what does the future hold for neurodegenerative disorders?

Alterations in WWOX protein and gene lead to mitochondrial dysfunction in amyotrophic lateral sclerosis

Altered expression of peroxisomal markers in a mouse model of amyotrophic lateral sclerosis

Assessing the role of cortical network dysfunction in amyotrophic lateral sclerosis through chemogenetic silencing of the corticospinal neurons

Body complexion and circulating lipids in the risk of Frontotemporal dementia and Amyotrophic Lateral Sclerosis

Characterization of extracellular vesicles released from spinal cord astrocytes of late symptomatic SOD1G93A mouse model of amyotrophic lateral sclerosis

Characterization of human induced pluripotent stem cell-derived microglia from a familial amyotrophic lateral sclerosis patient

Characterization of a therapeutic approach to target intracellular TDP-43 aggregates in cellular and animal models of Amyotrophic Lateral Sclerosis

Decreased noradrenaline levels contribute to cortical hyperexcitability in mouse models of amyotrophic lateral sclerosis

Defining the functional role of Tbk1 using a novel zebrafish model of Amyotrophic lateral sclerosis (ALS)

Does regular caffeine consumption impact cognition in Amyotrophic Lateral Sclerosis?

Effect of high-fat diet on hippocampal synaptic transmission and plasticity and neuroinflammation in a murine model of Amyotrophic Lateral Sclerosis

Feasibility and future role of high-density transcranial magnetic stimulation (HD-TMS) in Amyotrophic Lateral Sclerosis (ALS): A pilot study in healthy volunteers

Functional role of Amyotrophic Lateral sclerosis-associated optineurin variant in SH-SY5Y neuronal cells

Impact of Amyotrophic lateral sclerosis and Huntington’s disease on human adult hippocampal neurogenesis

In-vivo treatment with the GPR17 antagonist montelukast ameliorated the lifespan and delayed the disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis

Involvement of inhibitory neurons in amyotrophic lateral sclerosis and frontotemporal dementia linked to Fused in Sarcoma protein

Involvement of oligodendrocytes in Amyotrophic Lateral Sclerosis (ALS) linked to Fused in Sarcoma protein

Lipids as a novel biomarker for amyotrophic lateral sclerosis - evidence from the SOD1 mouse

Motor Imagery Preservation In Amyotrophic Lateral Sclerosis: Results From A Brain-Computer Interface Trial

The negative allosteric modulator CTEP ameliorates the reactive phenotype of i-astrocytes from patients affected by Amyotrophic Lateral Sclerosis

Novel functionalized nanoparticles targeted to 18KDa translocator protein (TSPO) to track and modulate neuroinflammation in animal models of familial Amyotrophic Lateral Sclerosis

Novel insights on the role and therapeutic potential of Glycoprotein nonmetastatic melanoma protein B (Gpnmb) in Amyotrophic Lateral Sclerosis

Peripheral inflammatory changes around motor axon terminals in the TDP-43 mouse model of amyotrophic lateral sclerosis

A simple, rapid and efficient differentiation protocol for the generation of induced pluripotent stem cell-derived motor neurons for amyotrophic lateral sclerosis modelling

Simultaneous activation of two complementary targets, Kv7.2/3 and TSPO: a promising and novel treatment for Amyotrophic Lateral Sclerosis

Sleep and orexinergic pathway alterations in mice models of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis and the central nervous system: The effect of the disease on cortical electrophysiological activity

The association between reduced respiratory function and cognition in amyotrophic lateral sclerosis

Auto-NRIP antibody is associated with amyotrophic lateral sclerosis disease progression

Disease-associated microglia-dependent and independent pathophysiology in spinal cord lesions in amyotrophic lateral sclerosis

Epigenetic targets of toxic metals implicated in amyotrophic lateral sclerosis development: A bioinformatic perspective

FUS-mutation carrying amyotrophic lateral sclerosis patient-derived motoneurons display lower survival, accumulate more DNA damage, and show elevated integrated stress response

Generation of patient-derived cortical and spinal organoids: A promising model for studying Amyotrophic Lateral Sclerosis (ALS)

Innovative models for amyotrophic lateral sclerosis research: Dermal fibroblasts and direct cell reprogramming

Investigating the molecular basis for selective vulnerability in FET-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)

The knocking-down of the restrictive element 1-silencing transcription factor (REST) improves symptoms and limits motor neuron degeneration in a mouse model of amyotrophic lateral sclerosis

The mitochondria-targeted antioxidant AntiOxCIN4 mitigates cardiac oxidative/nitrosative stress in the amyotrophic lateral sclerosis SOD1G93A mouse

One-carbon metabolism contribution to corticospinal neuron development in mouse models of amyotrophic lateral sclerosis

Sleep alterations in amyotrophic lateral sclerosis

SOD1opathy in sporadic amyotrophic lateral sclerosis with high plasma misfolded SOD1 protein level and specific electrophysiological pattern