A novel heterozygous mutation in the C-terminal region of HSPB8 leads to limb-girdle rimmed vacuolar myopathy.

Mutations in heat shock protein B8 were initially identified in inherited neuropathies and were more recently found to cause a predominantly distal myopathy with myofibrillar pathology and rimmed vacuoles. Rare patients also had proximal weakness. Only very few pathogenic variants have been identified in HSPB8.

Gradually Progressive Spastic Ataxia in a Young Man: Steadily Unsteady.

A 26-year-old right-handed man presented with progressive gait imbalance over 6 years. His examination was consistent with cerebellar and upper motor neuronal dysfunction. He had no significant family history.

Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SOD(G93A) mice co-expressing the Copper-Chaperone-for-SOD.

Over-expression of mutant copper, zinc superoxide dismutase (SOD) in mice induces ALS and has become the most widely used model of neurodegeneration. However, no pharmaceutical agent in 20 years has extended lifespan by more than a few weeks. The Copper-Chaperone-for-SOD (CCS) protein completes the maturation of SOD by inserting copper, but paradoxically human CCS causes mice co-expressing mutant SOD to die within two weeks of birth.

The RNA-binding protein TDP-43 selectively disrupts microRNA-1/206 incorporation into the RNA-induced silencing complex.

MicroRNA (miRNA) maturation is regulated by interaction of particular miRNA precursors with specific RNA-binding proteins. Following their biogenesis, mature miRNAs are incorporated into the RNA-induced silencing complex (RISC) where they interact with mRNAs to negatively regulate protein production. However, little is known about how mature miRNAs are regulated at the level of their activity.

Mitochondrial defects in transgenic mice expressing Cu,Zn superoxide dismutase mutations: the role of copper chaperone for SOD1.

Several hypotheses have been proposed for the mechanisms underlying mutant Cu,Zn Superoxide Dismutase-related Amyotrophic Lateral Sclerosis. These include aggregation pathology, mitochondrial dysfunctions, oxidative stress, and glutamate-mediated excitotoxicity. Mitochondrial disease may be a primary event in neurodegeneration, contributing to oxidative stress and apoptosis, or it may be caused by other cellular processes.

TDP-43, an ALS linked protein, regulates fat deposition and glucose homeostasis.

The identification of proteins which determine fat and lean body mass composition is critical to better understanding and treating human obesity. TDP-43 is a well-conserved RNA-binding protein known to regulate alternative splicing and recently implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). While TDP-43 knockout mice show early embryonic lethality, post-natal conditional knockout mice show weight loss, fat depletion, and rapid death, suggesting an important role for TDP-43 in regulating energy metabolism.

Biochemical properties and in vivo effects of the SOD1 zinc-binding site mutant (H80G).

This study presents the initial characterization of transgenic mice with mutations in a primary zinc-binding residue (H80), either alone or with a G93A mutation. H80G;G93A superoxide dismutase 1 (SOD1) transgenic mice developed paralysis with motor neuron loss, and ubiquitin inclusion-type rather than mitochondrial vacuolar pathology. Unlike G93A SOD1-related disease, the course was not accelerated by over-expression of copper chaperone for SOD1.

Huntington chorea presenting with motor neuron disease.

Background: There have been a few case reports of motor neuron disease in association with Huntington disease (HD).

Objective: To describe a patient presenting with prominent fasciculations, chorea, and possible amyotrophic lateral sclerosis (ALS) in whom genetic testing revealed HD mutation.

Design: Case report.

Progressive motor weakness in transgenic mice expressing human TDP-43.

Familial ALS patients with TDP-43 gene mutations and sporadic ALS patients share common TDP-43 neuronal pathology. To delineate mechanisms underlying TDP-43 proteinopathies, transgenic mice expressing A315T, M337V or wild type human TDP-43 were generated. Multiple TDP-43 founders developed a severe early motor phenotype that correlated with TDP-43 levels in spinal cord.

Pharmacological prion protein silencing accelerates central nervous system autoimmune disease via T cell receptor signalling.

The primary biological function of the endogenous cellular prion protein has remained unclear. We investigated its biological function in the generation of cellular immune responses using cellular prion protein gene-specific small interfering ribonucleic acid in vivo and in vitro. Our results were confirmed by blocking cellular prion protein with monovalent antibodies and by using cellular prion protein-deficient and -transgenic mice.

MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of motor neurons, denervation of target muscles, muscle atrophy, and paralysis. Understanding ALS pathogenesis may require a fuller understanding of the bidirectional signaling between motor neurons and skeletal muscle fibers at neuromuscular synapses. Here, we show that a key regulator of this signaling is miR-206, a skeletal muscle-specific microRNA that is dramatically induced in a mouse model of ALS.

Redox susceptibility of SOD1 mutants is associated with the differential response to CCS over-expression in vivo.

Over-expression of CCS in G93A SOD1 mice accelerates neurological disease and enhances mitochondrial pathology. We studied the effect of CCS over-expression in transgenic mice expressing G37R, G86R or L126Z SOD1 mutations in order to understand factors which influence mitochondrial dysfunction. Over-expression of CCS markedly decreased survival and produced mitochondrial vacuolation in G37R SOD1 mice but not in G86R or L126Z SOD1 mice.

The death domain-containing kinase RIP1 regulates p27(Kip1) levels through the PI3K-Akt-forkhead pathway.

Elucidating the cross-talk between inflammatory and cell proliferation pathways might provide important insights into the pathogenesis of inflammation-induced cancer. Here, we show that the receptor-interacting protein 1 (RIP1)-an essential mediator of inflammation-induced nuclear factor-kappaB (NF-kappaB) activation-regulates p27(Kip1) levels and cell-cycle progression. RIP1 regulates p27(Kip1) levels by an NF-kappaB-independent signal that involves activation of the phosphatidylinositol 3-kinase (PI3K)-Akt-forkhead pathway.

Biological effects of CCS in the absence of SOD1 enzyme activation: implications for disease in a mouse model for ALS.

The CCS copper chaperone is critical for maturation of Cu, Zn-superoxide dismutase (SOD1) through insertion of the copper co-factor and oxidization of an intra-subunit disulfide. The disulfide helps stabilize the SOD1 polypeptide, which can be particularly important in cases of amyotrophic lateral sclerosis (ALS) linked to misfolding of mutant SOD1. Surprisingly, however, over-expressed CCS was recently shown to greatly accelerate disease in a G93A SOD1 mouse model for ALS.

Isolated cytochrome c oxidase deficiency in G93A SOD1 mice overexpressing CCS protein.

G93A SOD1 transgenic mice overexpressing CCS protein develop an accelerated disease course that is associated with enhanced mitochondrial pathology and increased mitochondrial localization of mutant SOD1. Because these results suggest an effect of mutant SOD1 on mitochondrial function, we assessed the enzymatic activities of mitochondrial respiratory chain complexes in the spinal cords of CCS/G93A SOD1 and control mice. CCS/G93A SOD1 mouse spinal cord demonstrates a 55% loss of complex IV (cytochrome c oxidase) activity compared with spinal cord from age-matched non-transgenic or G93A SOD1 mice.

Assessing the role of immuno-proteasomes in a mouse model of familial ALS.

The accumulation of protein aggregates is thought to be an important component in the pathogenesis of mutant SOD1-induced disease. Mutant SOD1 aggregates appear to be cleared by proteasomes, at least in vitro, suggesting a potentially important role for proteasome degradation pathways in vivo. G93A SOD1 transgenic mice show an increase in proteasome activity and induction of immuno-proteasome subunits within spinal cord as they develop neurological symptoms.

Overexpression of CCS in G93A-SOD1 mice leads to accelerated neurological deficits with severe mitochondrial pathology.

Cu, Zn superoxide dismutase (SOD1) has been detected within spinal cord mitochondria of mutant SOD1 transgenic mice, a model of familial ALS. The copper chaperone for SOD1 (CCS) provides SOD1 with copper, facilitates the conversion of immature apo-SOD1 to a mature holoform, and influences in yeast the cytosolic/mitochondrial partitioning of SOD1. To determine how CCS affects G93A-SOD1-induced disease, we generated transgenic mice overexpressing CCS and crossed them to G93A-SOD1 or wild-type SOD1 transgenic mice.

Novel mutations that enhance or repress the aggregation potential of SOD1.

Mutations in SOD1 cause FALS by a gain of function likely related to protein misfolding and aggregation. SOD1 mutations encompass virtually every domain of the molecule, making it difficult to identify motifs important in SOD1 aggregation. Zinc binding to SOD1 is important for structural integrity, and is hypothesized to play a role in mutant SOD1 aggregation.

Non-neuronal induction of immunoproteasome subunits in an ALS model: possible mediation by cytokines.

Protein aggregation is a pathologic hallmark of familial amyotrophic lateral sclerosis caused by mutations in the Cu, Zn superoxide dismutase gene. Although SOD1-positive aggregates can be cleared by proteasomes, aggregates have been hypothesized to interfere with proteasome activity, leading to a vicious cycle that further enhances aggregate accumulation. To address this issue, we measured proteasome activity in transgenic mice expressing a G93A SOD1 mutation.

Aggregate formation in the spinal cord of mutant SOD1 transgenic mice is reversible and mediated by proteasomes.

Cu,Zn superoxide dismutase (SOD1) mutations cause one form of familial amyotrophic lateral sclerosis by a toxic gain of function that may be related to abnormal protein folding and aggregate formation. However, the processing pathways involved in SOD1 aggregate generation within spinal cord remain unclear. We have now developed an experimental system for studying SOD1 aggregate formation and clearance in intact spinal cord tissue.

Aggregate formation in Cu,Zn superoxide dismutase-related proteins.

Aggregation of Cu,Zn superoxide dismutase (SOD1) protein is a pathologic hallmark of familial amyotrophic lateral sclerosis linked to mutations in the SOD1 gene, although the structural motifs within mutant SOD1 that are responsible for its aggregation are unknown. Copper chaperone for SOD1 (CCS) and extracellular Cu,Zn superoxide dismutase (SOD3) have some sequence identity with SOD1, particularly in the regions of metal binding, but play no significant role in mutant SOD1-induced disease. We hypothesized that it would be possible to form CCS- or SOD3-positive aggregates by making these molecules resemble mutant SOD1 via the introduction of point mutations in codons homologous to a disease causing G85R SOD1 mutation.

Disease progression in a transgenic model of familial amyotrophic lateral sclerosis is dependent on both neuronal and non-neuronal zinc binding proteins.

Mutations in the Cu/Zn superoxide dismutase (SOD1) gene cause one form of familial amyotrophic lateral sclerosis, a progressive disorder of motor neurons leading to weakness and death of affected individuals. Experiments using both transgenic mice expressing mutant SOD1 and SOD1 knock-out mice have demonstrated that disease is caused by a toxic gain of function and not by a loss of normal SOD1 activity. Precise mechanisms underlying mutant SOD1 toxicity are unclear but may involve abnormal interactions between zinc and SOD1.