UsnRNP trafficking is regulated by stress granules and compromised by mutant ALS proteins.

Activation of the integrated stress response (ISR), alterations in nucleo-cytoplasmic (N/C) transport and changes in alternative splicing regulation are all common traits of the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). However, whether these processes act independently from each other, or are part of a coordinated mechanism of gene expression regulation that is affected in pathogenic conditions, is still rather undefined. To answer these questions, in this work we set out to characterise the functional connections existing between ISR activation and nucleo-cytosol trafficking and nuclear localization of spliceosomal U-rich small nuclear ribonucleoproteins (UsnRNPs), the core constituents of the spliceosome, and to study how ALS-linked mutant proteins affect this interplay.

The S100A4 Transcriptional Inhibitor Niclosamide Reduces Pro-Inflammatory and Migratory Phenotypes of Microglia: Implications for Amyotrophic Lateral Sclerosis.

S100A4, belonging to a large multifunctional S100 protein family, is a Ca-binding protein with a significant role in stimulating the motility of cancer and immune cells, as well as in promoting pro-inflammatory properties in different cell types. In the CNS, there is limited information concerning S100A4 presence and function. In this study, we analyzed the expression of S100A4 and the effect of the S100A4 transcriptional inhibitor niclosamide in murine activated primary microglia.

nNOS/GSNOR interaction contributes to skeletal muscle differentiation and homeostasis.

Neuronal nitric oxide synthase (nNOS) plays a crucial role in the maintenance of correct skeletal muscle function due, at least in part, to S-nitrosylation of specific protein targets. Similarly, we recently provided evidence for a muscular phenotype in mice lacking the denitrosylase S-nitrosoglutathione reductase (GSNOR). Here, we demonstrate that nNOS and GSNOR are concomitantly expressed during differentiation of C2C12.

50-Hz magnetic field impairs the expression of iron-related genes in the in vitro SOD1 model of amyotrophic lateral sclerosis.

Purpose: We characterized the response to the extremely low frequency magnetic field (ELF-MF) in an in vitro model of familial Amyotrophic Lateral Sclerosis (fALS), carrying two mutant variants of the superoxide dismutase 1 (SOD1) gene.

Materials And Methods: SH-SY5Y human neuroblastoma cells, stably over-expressing the wild type, the G93A or the H46R mutant SOD1 cDNA, were exposed to either the ELF-MF (50 Hz, 1 mT) or the sham control field, up to 72 h. Analysis of (i) viability, proliferation and apoptosis, (ii) reactive oxygen species generation, and (iii) assessment of the iron metabolism, were carried out in all clones in response to the MF exposure.

Epigenetic Changes Associated with the Expression of Amyotrophic Lateral Sclerosis (ALS) Causing Genes.

Neurodegenerative disorders, including Amyotrophic Lateral Sclerosis (ALS), have been associated to alterations in chromatin structure resulting in long-lasting changes in gene expression. ALS is predominantly a sporadic disease and environmental triggers may be involved in its onset. In this respect, alterations in the epigenome can provide the key to transform the genetic information into phenotype.

Differential toxicity of TAR DNA-binding protein 43 isoforms depends on their submitochondrial localization in neuronal cells.

TAR DNA-binding protein 43 (TDP-43) is an RNA-binding protein and a major component of protein aggregates found in amyotrophic lateral sclerosis and several other neurodegenerative diseases. TDP-43 exists as a full-length protein and as two shorter forms of 25 and 35 kDa. Full-length mutant TDP-43s found in amyotrophic lateral sclerosis patients re-localize from the nucleus to the cytoplasm and in part to mitochondria, where they exert a toxic role associated with neurodegeneration.

Publisher Correction: Functional interaction between FUS and SMN underlies SMA-like splicing changes in wild-type hFUS mice.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Mitochondria in the nervous system: From health to disease, part II.

In Part II of this Special Issue on "Mitochondria in the Nervous System: From Health to Disease", the editors bring together more reviews and original articles from researchers in the field of mitochondrial metabolism in the healthy and diseased nervous system. Subjects span from basic mitochondrial physiology to papers on mitochondrial dynamics and to those altered states of the nervous system that can be considered "mitopathologies". Finally, a few papers approach aspects of mitochondrial biology linked to the feasibility and validity of a mitochondrial therapy.

Mitochondria in the nervous system: From health to disease, Part I.

In Part I of this Special Issue on "Mitochondria in the Nervous System: From Health to Disease", the editors bring together contributions from experts in brain mitochondrial research to provide an up-to-date overview of mitochondrial functioning in physiology and pathology. The issue provides cutting edge reviews on classical areas of mitochondrial biology that include energy substrate utilization, calcium handling, mitochondria-endoplasmic reticulum communication, and cell death regulation. Additional reviews and original research articles touch upon key mitochondrial defects seen across multiple neurodegenerative conditions, including fragmentation, loss of respiratory capacity, calcium overload, elevated reactive oxygen species generation, perturbed NAD metabolism, altered protein acetylation, and compromised mitophagy.

Neuroinflammation in Amyotrophic Lateral Sclerosis: Role of Redox (dys)Regulation.

Significance: Amyotrophic lateral sclerosis (ALS) is due to degeneration of upper and lower motor neurons in the anterior horn of the spinal cord and in the motor cortex. Mechanisms leading to motor neuron death are complex and currently the disease is untreatable. Recent Advances: Work in genetic models of ALS indicates that an imbalance in the cross talk that physiologically exists between motor neurons and the surrounding cells is eventually detrimental to motor neurons.

Role of LRRK2 in the regulation of dopamine receptor trafficking.

Mutations in LRRK2 play a critical role in both familial and sporadic Parkinson's disease (PD). Up to date, the role of LRRK2 in PD onset and progression remains largely unknown. However, experimental evidence highlights a critical role of LRRK2 in the control of vesicle trafficking that in turn may regulate different aspects of neuronal physiology.

Functional interaction between FUS and SMN underlies SMA-like splicing changes in wild-type hFUS mice.

Several of the identified genetic factors in Amyotrophic Lateral Sclerosis (ALS) point to dysfunction in RNA processing as a major pathogenic mechanism. However, whether a precise RNA pathway is particularly affected remains unknown. Evidence suggests that FUS, that is mutated in familial ALS, and SMN, the causative factor in Spinal Muscular Atrophy (SMA), cooperate to the same molecular pathway, i.

SIRT3 and mitochondrial metabolism in neurodegenerative diseases.

The NAD-dependent deacetylase protein Sirtuin 3 (SIRT3) is emerging among the factors playing a key role in the regulation of mitochondrial function and in the prevention of oxidative stress. This deacetylase activates protein substrates directly involved in the production and detoxification of ROS, such as superoxide dismutase 2 and catalase, but also enzymes in the lipid beta-oxidation pathway. In this paper we review existing evidence on the role of SIRT3 in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington disease, including data from new experiments in a model for amyotrophic lateral sclerosis linked to mutations in superoxide dismutase 1.

Cysteine Modifications in the Pathogenesis of ALS.

Several proteins are found misfolded and aggregated in sporadic and genetic forms of amyotrophic lateral sclerosis (ALS). These include superoxide dismutase (SOD1), transactive response DNA-binding protein (TDP-43), fused in sarcoma/translocated in liposarcoma protein (FUS/TLS), p62, vasolin-containing protein (VCP), Ubiquilin-2 and dipeptide repeats produced by unconventional RAN-translation of the GGGGCC expansion in C9ORF72. Up to date, functional studies have not yet revealed a common mechanism for the formation of such diverse protein inclusions.

Pathways to mitochondrial dysfunction in ALS pathogenesis.

Alterations in the structure and functions of mitochondria are a typical trait of Amyotrophic Lateral Sclerosis, a neurodegenerative disease characterized by a prominent degeneration of upper and lower motor neurons. The known gene mutations that are responsible for a small fraction of ALS cases point to a complex interplay between different mechanisms in the disease pathogenesis. Here we will briefly overview the genetic and mechanistic evidence that make dysfunction of mitochondria a candidate major player in this process.

Old versus New Mechanisms in the Pathogenesis of ALS.

Amyotrophic Lateral Sclerosis (ALS) is recognized as a very complex disease. As we have learned in the past 20 years from studies in patients and in models based on the expression of mutant SOD1, ALS is not a purely motor neuron disease as previously thought. While undoubtedly motor neurons are lost in patients, a number of alterations in those cell-types that interact functionally with motor neurons (astrocytes, microglia, muscle fibers, oligodendrocytes) take place even long before onset of symptoms.

S-Nitrosoglutathione Reductase Plays Opposite Roles in SH-SY5Y Models of Parkinson's Disease and Amyotrophic Lateral Sclerosis.

Oxidative and nitrosative stresses have been reported as detrimental phenomena concurring to the onset of several neurodegenerative diseases. Here we reported that the ectopic modulation of the denitrosylating enzyme S-nitrosoglutathione reductase (GSNOR) differently impinges on the phenotype of two SH-SY5Y-based in vitro models of neurodegeneration, namely, Parkinson's disease (PD) and familial amyotrophic lateral sclerosis (fALS). In particular, we provide evidence that GSNOR-knocking down protects SH-SY5Y against PD toxins, while, by contrast, its upregulation is required for G93A-SOD1 expressing cells resistance to NO-releasing drugs.

Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS.

A common feature of non-coding repeat expansion disorders is the accumulation of RNA repeats as RNA foci in the nucleus and/or cytoplasm of affected cells. These RNA foci can be toxic because they sequester RNA-binding proteins, thus affecting various steps of post-transcriptional gene regulation. However, the precise step that is affected by C9orf72 GGGGCC (G4C2) repeat expansion, the major genetic cause of amyotrophic lateral sclerosis (ALS), is still poorly defined.

Oxidative stress and mitochondrial damage: importance in non-SOD1 ALS.

It is well known that mitochondrial damage (MD) is both the major contributor to oxidative stress (OS) (the condition arising from unbalance between production and removal of reactive oxygen species) and one of the major consequences of OS, because of the high dependance of mitochondrial function on redox-sensitive targets such as intact membranes. Conditions in which neuronal cells are not able to cope with MD and OS seem to lead or contribute to several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS), at least in the most studied superoxide dismutase 1 (SOD1)-linked genetic variant. As summarized in this review, new evidence indicates that MD and OS play a role also in non-SOD1 ALS and thus they may represent a target for therapy despite previous failures in clinical trials.

Mitochondrial dynamism and the pathogenesis of Amyotrophic Lateral Sclerosis.

Research on mitochondria in the last years has been characterized by the fundamental finding that the morphology of mitochondria is deeply connected to the regulation of a vast number of different processes, including oxidative phosphorylation and ATP production, calcium buffering, and apoptosis. This has immediately focused the attention of the neuroscience community to the possible involvement of mitochondrial dynamism, the process underlying morphological features of mitochondria, in neurodegeneration, where mitochondrial dysfunction is believed to represent an important contributing event, or even a primary causative factor. Amyotrophic Lateral Sclerosis (ALS), a disease of motor neurons and their neighboring cells, has long been considered as a neurodegenerative disease with an important mitochondrial issue.

Neuronal RNA-binding proteins in health and disease.

In mammalian cells in general and in neurons in particular, mRNA maturation, translation, and degradation are highly complex and dynamic processes. RNA-binding proteins (RBPs) play crucial roles in all these events. First, they participate in the choice of pre-mRNA splice sites and in the selection of the polyadenylation sites, determining which of the possible isoforms is produced from a given precursor mRNA.

The intriguing case of motor neuron disease: ALS and SMA come closer.

MNDs (motor neuron diseases) form a heterogeneous group of pathologies characterized by the progressive degeneration of motor neurons. More and more genetic factors associated with MND encode proteins that have a function in RNA metabolism, suggesting that disturbed RNA metabolism could be a common underlying problem in several, perhaps all, forms of MND. In the present paper we review recent developments showing a functional link between SMN (survival of motor neuron), the causative factor of SMA (spinal muscular atrophy), and FUS (fused in sarcoma), a genetic factor in ALS (amyotrophic lateral sclerosis).