scholarly journals Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS

2021 ◽  
Author(s):  
Kazuhide Asakawa ◽  
Hiroshi Handa ◽  
Koichi Kawakami
Keyword(s):  
Motor Neurons ◽  
Selective Vulnerability ◽  
Extracellular Milieu ◽  
Heterogeneous Nuclear Ribonucleoprotein ◽  
Evolutionarily Conserved ◽  
Selective Neuronal Vulnerability ◽  
Nuclear Ribonucleoprotein ◽  
Rnp Granules ◽  
Lateral Sclerosis

AbstractTransactive response DNA-binding protein 43 kDa (TDP-43) encoded by the TARDBP gene is an evolutionarily conserved heterogeneous nuclear ribonucleoprotein (hnRNP) that regulates multiple steps of RNA metabolism, and its cytoplasmic aggregation characterizes degenerating motor neurons in amyotrophic lateral sclerosis (ALS). In most ALS cases, cytoplasmic TDP-43 aggregation occurs in the absence of mutations in the coding sequence of TARDBP. Thus, a major challenge in ALS research is to understand the nature of pathological changes occurring in wild-type TDP-43 and to explore upstream events in intracellular and extracellular milieu that promote the pathological transition of TDP-43. Despite the inherent obstacles to analyzing TDP-43 dynamics in in vivo motor neurons due to their anatomical complexity and inaccessibility, recent studies using cellular and animal models have provided important mechanistic insights into potential links between TDP-43 and motor neuron vulnerability in ALS. This review is intended to provide an overview of the current literature on the function and regulation of TDP-43-containing RNP granules or membraneless organelles, as revealed by various models, and to discuss the potential mechanisms by which TDP-43 can cause selective vulnerability of motor neurons in ALS.

scholarly journals Mice deficient in Epg5 exhibit selective neuronal vulnerability to degeneration

2013 ◽  
Vol 200 (6) ◽  
pp. 731-741 ◽  
Author(s):  
Hongyu Zhao ◽  
Yan G. Zhao ◽  
Xingwei Wang ◽  
Lanjun Xu ◽  
Lin Miao ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Motor Neurons ◽  
Pyramidal Neurons ◽  
Late Onset ◽  
Selective Vulnerability ◽  
Cortical Layer ◽  
Autophagic Flux ◽  
Neuronal Populations ◽  
Selective Neuronal Vulnerability ◽  
Lateral Sclerosis

The molecular mechanism underlying the selective vulnerability of certain neuronal populations associated with neurodegenerative diseases remains poorly understood. Basal autophagy is important for maintaining axonal homeostasis and preventing neurodegeneration. In this paper, we demonstrate that mice deficient in the metazoan-specific autophagy gene Epg5/epg-5 exhibit selective damage of cortical layer 5 pyramidal neurons and spinal cord motor neurons. Pathologically, Epg5 knockout mice suffered muscle denervation, myofiber atrophy, late-onset progressive hindquarter paralysis, and dramatically reduced survival, recapitulating key features of amyotrophic lateral sclerosis (ALS). Epg5 deficiency impaired autophagic flux by blocking the maturation of autophagosomes into degradative autolysosomes, leading to accumulation of p62 aggregates and ubiquitin-positive inclusions in neurons and glial cells. Epg5 knockdown also impaired endocytic trafficking. Our study establishes Epg5-deficient mice as a model for investigating the pathogenesis of ALS and indicates that dysfunction of the autophagic–endolysosomal system causes selective damage of neurons associated with neurodegenerative diseases.

scholarly journals LanCL1 promotes motor neuron survival and extends the lifespan of amyotrophic lateral sclerosis mice

2019 ◽  
Vol 27 (4) ◽  
pp. 1369-1382 ◽  
Author(s):  
Honglin Tan ◽  
Mina Chen ◽  
Dejiang Pang ◽  
Xiaoqiang Xia ◽  
Chongyangzi Du ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neuronal Survival ◽  
Disease Onset ◽  
Alternative Mechanism ◽  
Specific Expression ◽  
Motor Neuron Survival ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Improving neuronal survival in ALS remains a significant challenge. Previously, we identified Lanthionine synthetase C-like protein 1 (LanCL1) as a neuronal antioxidant defense gene, the genetic deletion of which causes apoptotic neurodegeneration in the brain. Here, we report in vivo data using the transgenic SOD1G93A mouse model of ALS indicating that CNS-specific expression of LanCL1 transgene extends lifespan, delays disease onset, decelerates symptomatic progression, and improves motor performance of SOD1G93A mice. Conversely, CNS-specific deletion of LanCL1 leads to neurodegenerative phenotypes, including motor neuron loss, neuroinflammation, and oxidative damage. Analysis reveals that LanCL1 is a positive regulator of AKT activity, and LanCL1 overexpression restores the impaired AKT activity in ALS model mice. These findings indicate that LanCL1 regulates neuronal survival through an alternative mechanism, and suggest a new therapeutic target in ALS.

scholarly journals Multiple single-stranded cis elements are associated with activated chromatin of the human c-myc gene in vivo.

1996 ◽  
Vol 16 (6) ◽  
pp. 2656-2669 ◽  
Author(s):  
G A Michelotti ◽  
E F Michelotti ◽  
A Pullner ◽  
R C Duncan ◽  
D Eick ◽  
...  
Keyword(s):  
Binding Protein ◽  
Single Strand ◽  
Upstream Sequence ◽  
Cis Elements ◽  
Sequence Element ◽  
S1 Nuclease ◽  
Heterogeneous Nuclear Ribonucleoprotein ◽  
Myc Gene ◽  
Nuclear Ribonucleoprotein

Transcription activation and repression of eukaryotic genes are associated with conformational and topological changes of the DNA and chromatin, altering the spectrum of proteins associated with an active gene. Segments of the human c-myc gene possessing non-B structure in vivo located with enzymatic and chemical probes. Sites hypertensive to cleavage with single-strand-specific S1 nuclease or the single-strand-selective agent potassium permanganate included the major promoters P1 and P2 as well as the far upstream sequence element (FUSE) and CT elements, which bind, respectively, the single-strand-specific factors FUSE-binding protein and heterogeneous nuclear ribonucleoprotein K in vitro. Active and inactive c-myc genes yielded different patterns of S1 nuclease and permanganate sensitivity, indicating alternative chromatin configurations of active and silent genes. The melting of specific cis elements of active c-myc genes in vivo suggested that transcriptionally associated torsional strain might assist strand separation and facilitate factor binding. Therefore, the interaction of FUSE-binding protein and heterogeneous nuclear ribonucleoprotein K with supercoiled DNA was studied. Remarkably, both proteins recognize their respective elements torsionally strained but not as liner duplexes. Single-strand- or supercoil-dependent gene regulatory proteins may directly link alterations in DNA conformation and topology with changes in gene expression.

scholarly journals Glial Cells—The Strategic Targets in Amyotrophic Lateral Sclerosis Treatment

2020 ◽  
Vol 9 (1) ◽  
pp. 261 ◽  
Author(s):  
Tereza Filipi ◽  
Zuzana Hermanova ◽  
Jana Tureckova ◽  
Ondrej Vanatko ◽  
Miroslava Anderova
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Current Knowledge ◽  
Gene Mutations ◽  
Cell Types ◽  
In Vivo Models ◽  
Cell Therapies ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease, which is characterized by the degeneration of motor neurons in the motor cortex and the spinal cord and subsequently by muscle atrophy. To date, numerous gene mutations have been linked to both sporadic and familial ALS, but the effort of many experimental groups to develop a suitable therapy has not, as of yet, proven successful. The original focus was on the degenerating motor neurons, when researchers tried to understand the pathological mechanisms that cause their slow death. However, it was soon discovered that ALS is a complicated and diverse pathology, where not only neurons, but also other cell types, play a crucial role via the so-called non-cell autonomous effect, which strongly deteriorates neuronal conditions. Subsequently, variable glia-based in vitro and in vivo models of ALS were established and used for brand-new experimental and clinical approaches. Such a shift towards glia soon bore its fruit in the form of several clinical studies, which more or less successfully tried to ward the unfavourable prognosis of ALS progression off. In this review, we aimed to summarize current knowledge regarding the involvement of each glial cell type in the progression of ALS, currently available treatments, and to provide an overview of diverse clinical trials covering pharmacological approaches, gene, and cell therapies.

The heterogeneous nuclear ribonucleoprotein-R is necessary for axonal β-actin mRNA translocation in spinal motor neurons

2010 ◽  
Vol 19 (10) ◽  
pp. 1951-1966 ◽  
Author(s):  
Michael Glinka ◽  
Thomas Herrmann ◽  
Natalja Funk ◽  
Steven Havlicek ◽  
Wilfried Rossoll ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Spinal Motor Neurons ◽  
Heterogeneous Nuclear Ribonucleoprotein ◽  
Spinal Motor ◽  
Actin Mrna ◽  
Nuclear Ribonucleoprotein

scholarly journals Characterization of LAMP1-labeled nondegradative lysosomal and endocytic compartments in neurons

2018 ◽  
Vol 217 (9) ◽  
pp. 3127-3139 ◽  
Author(s):  
Xiu-Tang Cheng ◽  
Yu-Xiang Xie ◽  
Bing Zhou ◽  
Ning Huang ◽  
Tamar Farfel-Becker ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Distribution Patterns ◽  
Confocal Imaging ◽  
Lysosomal Hydrolases ◽  
Differential Distribution ◽  
Gradient Fractionation ◽  
Endocytic Compartments ◽  
Lateral Sclerosis

Despite widespread distribution of LAMP1 and the heterogeneous nature of LAMP1-labeled compartments, LAMP1 is routinely used as a lysosomal marker, and LAMP1-positive organelles are often referred to as lysosomes. In this study, we use immunoelectron microscopy and confocal imaging to provide quantitative analysis of LAMP1 distribution in various autophagic and endolysosomal organelles in neurons. Our study demonstrates that a significant portion of LAMP1-labeled organelles do not contain detectable lysosomal hydrolases including cathepsins D and B and glucocerebrosidase. A bovine serum albumin–gold pulse–chase assay followed by ultrastructural analysis suggests a heterogeneity of degradative capacity in LAMP1-labeled endolysosomal organelles. Gradient fractionation displays differential distribution patterns of LAMP1/2 and cathepsins D/B in neurons. We further reveal that LAMP1 intensity in familial amyotrophic lateral sclerosis–linked motor neurons does not necessarily reflect lysosomal deficits in vivo. Our study suggests that labeling a set of lysosomal hydrolases combined with various endolysosomal markers would be more accurate than simply relying on LAMP1/2 staining to assess neuronal lysosome distribution, trafficking, and functionality under physiological and pathological conditions.

scholarly journals Neuronal over-expression of Oxr1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo

2019 ◽  
Vol 28 (21) ◽  
pp. 3584-3599 ◽  
Author(s):  
Matthew G Williamson ◽  
Mattéa J Finelli ◽  
James N Sleigh ◽  
Amy Reddington ◽  
David Gordon ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Gene Encoding ◽  
Over Expression ◽  
Neuromuscular Abnormalities ◽  
And Function ◽  
Lateral Sclerosis

Abstract A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and the related neurodegenerative disorder frontotemporal dementia, is the cellular mislocalization of transactive response DNA-binding protein 43 kDa (TDP-43). Additionally, multiple mutations in the TARDBP gene (encoding TDP-43) are associated with familial forms of ALS. While the exact role for TDP-43 in the onset and progression of ALS remains unclear, the identification of factors that can prevent aberrant TDP-43 localization and function could be clinically beneficial. Previously, we discovered that the oxidation resistance 1 (Oxr1) protein could alleviate cellular mislocalization phenotypes associated with TDP-43 mutations, and that over-expression of Oxr1 was able to delay neuromuscular abnormalities in the hSOD1G93A ALS mouse model. Here, to determine whether Oxr1 can protect against TDP-43-associated phenotypes in vitro and in vivo, we used the same genetic approach in a newly described transgenic mouse expressing the human TDP-43 locus harbouring an ALS disease mutation (TDP-43M337V). We show in primary motor neurons from TDP-43M337V mice that genetically-driven Oxr1 over-expression significantly alleviates cytoplasmic mislocalization of mutant TDP-43. We also further quantified newly-identified, late-onset neuromuscular phenotypes of this mutant line, and demonstrate that neuronal Oxr1 over-expression causes a significant reduction in muscle denervation and neuromuscular junction degeneration in homozygous mutants in parallel with improved motor function and a reduction in neuroinflammation. Together these data support the application of Oxr1 as a viable and safe modifier of TDP-43-associated ALS phenotypes.

scholarly journals Heterogeneous nuclear ribonucleoprotein D0B is a sequence-specificDNA-binding protein

1999 ◽  
Vol 338 (2) ◽  
pp. 417-425 ◽  
Author(s):  
Mate TOLNAY ◽  
Lyudmila A. VERESHCHAGINA ◽  
George C. TSOKOS
Keyword(s):  
Dna Sequences ◽  
Rna Binding ◽  
Binding Protein ◽  
Double Helix ◽  
Physiological Role ◽  
Single Stranded Dna ◽  
Heterogeneous Nuclear Ribonucleoprotein ◽  
Double Stranded Dna ◽  
Nuclear Ribonucleoprotein

Complement receptor 2 (CR2) is important in the regulation of the B lymphocyte response; the regulation of its expression is therefore of central importance. We recently reported that a 42 kDa heterogeneous nuclear ribonucleoprotein (hnRNP) is involved in the transcriptional regulation of the human CR2 gene [Tolnay, Lambris and Tsokos (1997) J. Immunol. 159, 5492–5501]. We cloned the cDNA encoding this protein and found it to be identical with hnRNP D0B, a sequence-specific RNA-binding protein. By using a set of mutated oligonucleotides, we demonstrated that the recombinant hnRNP D0B displays sequence specificity for double-stranded oligonucleotide defined by the CR2 promoter. We conducted electrophoretic mobility-shift assays to estimate the apparent Kd of hnRNP D0B for the double-stranded DNA motif and found it to be 59 nM. Interestingly, hnRNP D0B displayed affinities of 28 and 18 nM for the sense and anti-sense strands of the CR2 promoter-defined oligonucleotide respectively. The significantly greater binding affinity of hnRNP D0B for single-stranded DNA than for double-stranded DNA suggests that the protein might melt the double helix. The intranuclear concentration of sequence-specific protein was estimated to be 250–400 nM, indicating that the protein binds to the CR2 promoter in vivo. Co-precipitation of a complex formed in vivo between hnRNP D0B and the TATA-binding protein demonstrates that hnRNP D0B interacts with the basal transcription apparatus. Our results suggest a new physiological role for hnRNP D0B that involves binding to double- and single-stranded DNA sequences in a specific manner and functioning as a transcription factor.

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