N-acetylaspartate mitigates pro-inflammatory responses in microglial cells by intersecting lipid metabolism and acetylation processes.

Background: Microglia play a crucial role in brain development and repair by facilitating processes such as synaptic pruning and debris clearance. They can be activated in response to various stimuli, leading to either pro-inflammatory or anti-inflammatory responses associated with specific metabolic alterations. The imbalances between microglia activation states contribute to chronic neuroinflammation, a hallmark of neurodegenerative diseases.

Neuroprotective effects of niclosamide on disease progression via inflammatory pathways modulation in SOD1-G93A and FUS-associated amyotrophic lateral sclerosis models.

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease influenced by genetic, epigenetic, and environmental factors, resulting in dysfunction in cellular and molecular pathways. The limited efficacy of current treatments highlights the need for combination therapies targeting multiple aspects of the disease. Niclosamide, an anthelminthic drug listed as an essential medicine, has been repurposed in clinical trials for different diseases due to its anti-inflammatory and anti-fibrotic properties.

Toxic Species Affect ArfGAP-1 Function.

Compelling evidence indicates that defects in nucleocytoplasmic transport contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). In particular, hexanucleotide (G4C2) repeat expansions in , the most common cause of genetic ALS, have a widespread impact on the transport machinery that regulates the nucleocytoplasmic distribution of proteins and RNAs. We previously reported that the expression of G4C2 hexanucleotide repeats in cultured human and mouse cells caused a marked accumulation of poly(A) mRNAs in the cell nuclei.

Inflammation in the CNS and PNS: From Molecular Basis to Therapy.

Our understanding of the pathophysiology of the nervous system has advanced significantly in the last few years, but there are still many unanswered questions [...

Neuroinflammation in Friedreich's Ataxia.

Friedreich's ataxia (FRDA) is a rare genetic disorder caused by mutations in the gene frataxin, encoding for a mitochondrial protein involved in iron handling and in the biogenesis of iron-sulphur clusters, and leading to progressive nervous system damage. Although the overt manifestations of FRDA in the nervous system are mainly observed in the neurons, alterations in non-neuronal cells may also contribute to the pathogenesis of the disease, as recently suggested for other neurodegenerative disorders. In FRDA, the involvement of glial cells can be ascribed to direct effects caused by frataxin loss, eliciting different aberrant mechanisms.

The Contribution of Non-Neuronal Cells in Neurodegeneration: From Molecular Pathogenesis to Therapeutic Challenges.

Neuron loss occurring in neurodegenerative diseases represents just the final step in a series of events involving several cell types, other than neurons, that actively contribute to the overall pathogenic mechanisms by establishing harmful non-cell autonomous effects [...

Targeting S100A4 with niclosamide attenuates inflammatory and profibrotic pathways in models of amyotrophic lateral sclerosis.

Background: An increasing number of studies evidences that amyotrophic lateral sclerosis (ALS) is characterized by extensive alterations in different cell types and in different regions besides the CNS. We previously reported the upregulation in ALS models of a gene called fibroblast-specific protein-1 or S100A4, recognized as a pro-inflammatory and profibrotic factor. Since inflammation and fibrosis are often mutual-sustaining events that contribute to establish a hostile environment for organ functions, the comprehension of the elements responsible for these interconnected pathways is crucial to disclose novel aspects involved in ALS pathology.

S100A4 in the Physiology and Pathology of the Central and Peripheral Nervous System.

S100A4 is a member of the large family of S100 proteins, exerting a broad range of intracellular and extracellular functions that vary upon different cellular contexts. While S100A4 has long been implicated mainly in tumorigenesis and metastatization, mounting evidence shows that S100A4 is a key player in promoting pro-inflammatory phenotypes and organ pro-fibrotic pathways in the liver, kidney, lung, heart, tendons, and synovial tissues. Regarding the nervous system, there is still limited information concerning S100A4 presence and function.

Microglial Pruning: Relevance for Synaptic Dysfunction in Multiple Sclerosis and Related Experimental Models.

Microglia, besides being able to react rapidly to a wide range of environmental changes, are also involved in shaping neuronal wiring. Indeed, they actively participate in the modulation of neuronal function by regulating the elimination (or "pruning") of weaker synapses in both physiologic and pathologic processes. Mounting evidence supports their crucial role in early synaptic loss, which is emerging as a hallmark of several neurodegenerative diseases, including multiple sclerosis (MS) and its preclinical models.

Fibrotic Scar in Neurodegenerative Diseases.

The process of uncontrolled internal scarring, called fibrosis, is now emerging as a pathological feature shared by both peripheral and central nervous system diseases. In the CNS, damaged neurons are not replaced by tissue regeneration, and scar-forming cells such as endothelial cells, inflammatory immune cells, stromal fibroblasts, and astrocytes can persist chronically in brain and spinal cord lesions. Although this process was extensively described in acute CNS damages, novel evidence indicates the involvement of a fibrotic reaction in chronic CNS injuries as those occurring during neurodegenerative diseases, where inflammation and fibrosis fuel degeneration.

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.

The S100B story: from biomarker to active factor in neural injury.

S100B is a Ca -binding protein mainly concentrated in astrocytes. Its levels in biological fluids (cerebrospinal fluid, peripheral and cord blood, urine, saliva, amniotic fluid) are recognized as a reliable biomarker of active neural distress. Although the wide spectrum of diseases in which the protein is involved (acute brain injury, neurodegenerative diseases, congenital/perinatal disorders, psychiatric disorders) reduces its specificity, its levels remain an important aid in monitoring the trend of the disorder.

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.

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.

The Dual Role of Microglia in ALS: Mechanisms and Therapeutic Approaches.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a non-cell autonomous motor neuron loss. While it is generally believed that the disease onset takes place inside motor neurons, different cell types mediating neuroinflammatory processes are considered deeply involved in the progression of the disease. On these grounds, many treatments have been tested on ALS animals with the aim of inhibiting or reducing the pro-inflammatory action of microglia and astrocytes and counteract the progression of the disease.

The Astrocytic S100B Protein with Its Receptor RAGE Is Aberrantly Expressed in SOD1 Models, and Its Inhibition Decreases the Expression of Proinflammatory Genes.

Neuroinflammation is one of the major players in amyotrophic lateral sclerosis (ALS) pathogenesis, and astrocytes are significantly involved in this process. The astrocytic protein S100B can be released in pathological states activating the receptor for advanced glycation end products (RAGE). Different indications point to an aberrant expression of S100B and RAGE in ALS.

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.

Copper at synapse: Release, binding and modulation of neurotransmission.

Over the last decade, a piece of the research studying copper role in biological systems was devoted to unravelling a still elusive, but extremely intriguing, aspect that is the involvement of copper in synaptic function. These studies were prompted to provide a rationale to the finding that copper is released in the synaptic cleft upon depolarization. The copper pump ATP7A, which mutations are responsible for diseases with a prominent neurodegenerative component, seems to play a pivotal role in the release of copper at synapses.