Loss of TMEM106B exacerbates C9ALS/FTD DPR pathology by disrupting autophagosome maturation.

Disruption to protein homeostasis caused by lysosomal dysfunction and associated impairment of autophagy is a prominent pathology in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). The most common genetic cause of ALS/FTD is a G4C2 hexanucleotide repeat expansion in (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of G4C2 repeat transcripts gives rise to dipeptide repeat (DPR) proteins that have been shown to be toxic and may contribute to disease etiology.

An interaction between synapsin and C9orf72 regulates excitatory synapses and is impaired in ALS/FTD.

Dysfunction and degeneration of synapses is a common feature of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). A GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene is the main genetic cause of ALS/FTD (C9ALS/FTD). The repeat expansion leads to reduced expression of the C9orf72 protein.

-derived poly-GA DPRs undergo endocytic uptake in iAstrocytes and spread to motor neurons.

Dipeptide repeat (DPR) proteins are aggregation-prone polypeptides encoded by the pathogenic GGGGCC repeat expansion in the gene, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. In this study, we focus on the role of poly-GA DPRs in disease spread. We demonstrate that recombinant poly-GA oligomers can directly convert into solid-like aggregates and form characteristic β-sheet fibrils in vitro.

Lamb1a regulates atrial growth by limiting second heart field addition during zebrafish heart development.

During early vertebrate heart development, the heart transitions from a linear tube to a complex asymmetric structure, a morphogenetic process that occurs simultaneously with growth of the heart. Cardiac growth during early heart morphogenesis is driven by deployment of cells from the second heart field (SHF) into both poles of the heart. Laminin is a core component of the extracellular matrix and, although mutations in laminin subunits are linked with cardiac abnormalities, no role for laminin has been identified in early vertebrate heart morphogenesis.

The GLP-1 receptor agonist, liraglutide, fails to slow disease progression in SOD1 and TDP-43 transgenic mouse models of ALS.

GLP-1 receptor agonists used for the treatment of diabetes, have shown some neuroprotective effects in cellular and animal models of Alzheimer's disease (AD) and Parkinson's disease (PD). There are currently few studies investigating GLP-1 receptor agonists in the treatment of ALS, where these neuroprotective effects may be beneficial. Here we investigate the effects of liraglutide, a GLP-1 receptor agonist, in two well characterised transgenic mouse models of ALS (SOD1 and TDP-43) to determine if liraglutide could be a potential treatment in ALS patients.

Loss of Deacetylation Enzymes Hdac6 and Sirt2 Promotes Acetylation of Cytoplasmic Tubulin, but Suppresses Axonemal Acetylation in Zebrafish Cilia.

Cilia are evolutionarily highly conserved organelles with important functions in many organs. The extracellular component of the cilium protruding from the plasma membrane comprises an axoneme composed of microtubule doublets, arranged in a 9 + 0 conformation in primary cilia or 9 + 2 in motile cilia. These microtubules facilitate transport of intraflagellar cargoes along the axoneme.

Adipose-derived stem cells protect motor neurons and reduce glial activation in both and models of ALS.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative condition for which new therapeutic options are urgently needed. We injected GFP adipose-derived stem cells (EGFP-ADSCs) directly into the cerebrospinal fluid (CSF) of transgenic SOD1 mice, a well-characterized model of familial ALS. Despite short-term survival of the injected cells and limited engraftment efficiency, EGFP-ADSCs improved motor function and delayed disease onset by promoting motor neuron (MN) survival and reducing glial activation.

Spastin recovery in hereditary spastic paraplegia by preventing neddylation-dependent degradation.

Hereditary Spastic Paraplegia (HSP) is a neurodegenerative disease most commonly caused by autosomal dominant mutations in the gene encoding the microtubule-severing protein spastin. We hypothesise that -HSP is attributable to reduced spastin function because of haploinsufficiency; thus, therapeutic approaches which elevate levels of the wild-type spastin allele may be an effective therapy. However, until now, how spastin levels are regulated is largely unknown.

Neutrophils use selective autophagy receptor Sqstm1/p62 to target for degradation in zebrafish.

Macroautophagy/autophagy functions to degrade cellular components and intracellular pathogens. Autophagy receptors, including SQSTM1/p62, target intracellular pathogens. is a significant pathogen of humans, especially in immunocompromise.

Methodological standards, quality of reporting and regulatory compliance in animal research on amyotrophic lateral sclerosis: a systematic review.

Objectives: The amyotrophic lateral sclerosis (ALS) research community was one of the first to adopt methodology guidelines to improve preclinical research reproducibility. We here present the results of a systematic review to investigate how the standards in this field changed over the 10-year period during which the guidelines were first published (2007) and updated (2010).

Methods: We searched for papers reporting ALS research on SOD1 (superoxide dismutase 1) mice published between 2005 and 2015 on the ISI Web of Science database, resulting in a sample of 569 papers to review, after triage.

Use of zebrafish models to investigate rare human disease.

Rare diseases are collectively common and often extremely debilitating. Following the emergence of next-generation sequencing (NGS) technologies, the variants underpinning rare genetic disorders are being unearthed at an accelerating rate. However, many rare conditions lack effective treatments due to their poorly understood pathophysiology.

C9orf72 plays a central role in Rab GTPase-dependent regulation of autophagy.

A GGGGCC hexanucleotide repeat expansion in the first intron of the C9orf72 gene is the most common genetic defect associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS/FTD). Haploinsufficiency and a resulting loss of C9orf72 protein function has been suggested as a possible pathogenic mechanism in C9ALS/FTD. C9ALS/FTD patients exhibit specific ubiquitin and p62/sequestosome-1 positive but TDP-43 negative inclusions in the cerebellum and hippocampus, indicating possible autophagy deficits in these patients.

The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy.

A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). C9orf72 encodes two C9orf72 protein isoforms of unclear function. Reduced levels of C9orf72 expression have been reported in C9ALS/FTD patients, and although C9orf72 haploinsufficiency has been proposed to contribute to C9ALS/FTD, its significance is not yet clear.

AAV9-mediated central nervous system-targeted gene delivery via cisterna magna route in mice.

Current barriers to the use of adeno-associated virus serotype 9 (AAV9) in clinical trials for treating neurological disorders are its high expression in many off-target tissues such as liver and heart, and lack of cell specificity within the central nervous system (CNS) when using ubiquitous promoters such as human cytomegalovirus (CMV) or chicken-β-actin hybrid (CAG). To enhance targeting the transgene expression in CNS cells, self-complementary (sc) AAV9 vectors, scAAV9-GFP vectors carrying neuronal Hb9 and synapsin 1, and nonspecific CMV and CAG promoters were constructed. We demonstrate that synapsin 1 and Hb9 promoters exclusively targeted neurons in vitro, although their strengths were up to 10-fold lower than that of CMV.

Altered age-related changes in bioenergetic properties and mitochondrial morphology in fibroblasts from sporadic amyotrophic lateral sclerosis patients.

Mitochondria play a key role in aging, which is a well-established risk factor in amyotrophic lateral sclerosis (ALS). We have previously modeled metabolic dysregulation in ALS using fibroblasts isolated from sporadic ALS (SALS) and familial ALS patients. In the present study, we show that fibroblasts from SALS patients have an altered metabolic response to aging.

Early detection of motor dysfunction in the SOD1G93A mouse model of Amyotrophic Lateral Sclerosis (ALS) using home cage running wheels.

The SOD1G93A mouse has been used since 1994 for preclinical testing in amyotrophic lateral sclerosis (ALS). Despite recent genetic advances in our understanding of ALS, transgenic mice expressing mutant SOD1 remain the best available, and most widely used, vertebrate model of the disease. We previously described an optimised and rapid approach for preclinical studies in the SOD1G93A mouse.

Superoxide dismutase 1 mutation in a cellular model of amyotrophic lateral sclerosis shifts energy generation from oxidative phosphorylation to glycolysis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder involving the progressive degeneration of motor neurons in the brain and spinal cord. Mitochondrial dysfunction plays a key role in ALS disease progression and has been observed in several ALS cellular and animal models. Here, we show that fibroblasts isolated from ALS cases with a Cu/Zn superoxide dismutase (SOD1) I113T mutation recapitulate these mitochondrial defects.

Abnormalities in whisking behaviour are associated with lesions in brain stem nuclei in a mouse model of amyotrophic lateral sclerosis.

The transgenic SOD1(G93A) mouse is a model of human amyotrophic lateral sclerosis (ALS) and recapitulates many of the pathological hallmarks observed in humans, including motor neuron degeneration in the brain and the spinal cord. In mice, neurodegeneration particularly impacts on the facial nuclei in the brainstem. Motor neurons innervating the whisker pad muscles originate in the facial nucleus of the brain stem, with contractions of these muscles giving rise to "whisking" one of the fastest movements performed by mammals.

The effect of SOD1 mutation on cellular bioenergetic profile and viability in response to oxidative stress and influence of mutation-type.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. Substantial evidence implicates oxidative stress and mitochondrial dysfunction as early events in disease progression. Our aim was to ascertain whether mutation of the SOD1 protein increases metabolic functional susceptibility to oxidative stress.

Axonal Transport Defects in a Mitofusin 2 Loss of Function Model of Charcot-Marie-Tooth Disease in Zebrafish.

Charcot-Marie-Tooth disease (CMT) represents a group of neurodegenerative disorders typically characterised by demyelination (CMT1) or distal axon degeneration (CMT2) of motor and sensory neurons. The majority of CMT2 cases are caused by mutations in mitofusin 2 (MFN2); an essential gene encoding a protein responsible for fusion of the mitochondrial outer membrane. The mechanism of action of MFN2 mutations is still not fully resolved.

S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis.

Compelling evidence indicates that oxidative stress contributes to motor neuron injury in amyotrophic lateral sclerosis (ALS), but antioxidant therapies have not yet achieved therapeutic benefit in the clinic. The nuclear erythroid 2-related-factor 2 (Nrf2) transcription factor is a key regulator of an important neuroprotective response by driving the expression of multiple cytoprotective genes via its interaction with the antioxidant response element (ARE). Dysregulation of the Nrf2-ARE system has been identified in ALS models and human disease.

Tardbpl splicing rescues motor neuron and axonal development in a mutant tardbp zebrafish.

Mutations in the transactive response DNA binding protein-43 (TARDBP/TDP-43) gene, which regulates transcription and splicing, causes a familial form of amyotrophic lateral sclerosis (ALS). Here, we characterize and report the first tardbp mutation in zebrafish, which introduces a premature stop codon (Y220X), eliminating expression of the Tardbp protein. Another TARDBP ortholog, tardbpl, in zebrafish is shown to encode a Tardbp-like protein which is truncated compared with Tardbp itself and lacks part of the C-terminal glycine-rich domain (GRD).

No evidence for cardiac dysfunction in Kif6 mutant mice.

A KIF6 variant in man has been reported to be associated with adverse cardiovascular outcomes after myocardial infarction. No clear biological or physiological data exist for Kif6. We sought to investigate the impact of a deleterious KIF6 mutation on cardiac function in mice.

Discovery of Western European R1b1a2 Y chromosome variants in 1000 genomes project data: an online community approach.

The authors have used an online community approach, and tools that were readily available via the Internet, to discover genealogically and therefore phylogenetically relevant Y-chromosome polymorphisms within core haplogroup R1b1a2-L11/S127 (rs9786076). Presented here is the analysis of 135 unrelated L11 derived samples from the 1000 Genomes Project. We were able to discover new variants and build a much more complex phylogenetic relationship for L11 sub-clades.

Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a genetically diverse disease. At least 15 ALS-associated gene loci have so far been identified, and the causative gene is known in approximately 30% of familial ALS cases. Less is known about the factors underlying the sporadic form of the disease.