Microglial overexpression of fALS-linked mutant SOD1 induces SOD1 processing impairment, activation and neurotoxicity and is counteracted by the autophagy inducer trehalose

Massenzio, Francesca; Peña-Altamira, Emiliano; Petralla, Sabrina; Virgili, Marco; Zuccheri, Giampaolo; Miti, Andrea; Polazzi, Elisabetta; Mengoni, Ilaria; Piffaretti, Deborah; Monti, Barbara

doi:10.1016/j.bbadis.2018.10.013

Cited by 35 publications

(25 citation statements)

References 117 publications

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“…SOD1 overexpressing microglial cells have been found to release SOD1-containing exosomes as well [48]. Besides, they have shown toxicity in co-culture with primary neurons, which can be alleviated by treatment with the autophagy-inducer trehalose [48]. These findings strongly support the role of EVs in misfolded protein propagation following a prion-like fashion.…”

Section: Evidence Of Prion-like Ev-mediated Misfolded Protein Propagamentioning

confidence: 63%

“…Further, cell exposure to conditioned media derived from SOD1 overexpressing HEK293 cells induces intracellular accumulation of misfolded SOD1, while this does not occur after conditioned media depletion from EVs [47]. SOD1 overexpressing microglial cells have been found to release SOD1-containing exosomes as well [48]. Besides, they have shown toxicity in co-culture with primary neurons, which can be alleviated by treatment with the autophagy-inducer trehalose [48].…”

Section: Evidence Of Prion-like Ev-mediated Misfolded Protein Propagamentioning

confidence: 99%

See 1 more Smart Citation

Extracellular vesicles and amyotrophic lateral sclerosis: from misfolded protein vehicles to promising clinical biomarkers

Gagliardi

Bresolin

Comi

et al. 2020

Cell. Mol. Life Sci.

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Extracellular vesicles (EVs) are small reservoirs of different molecules and important mediators of cell-to-cell communication. As putative vehicles of misfolded protein propagation between cells, they have drawn substantial attention in the field of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Moreover, exosome-mediated non-coding RNA delivery may play a crucial role in ALS, given the relevance of RNA homeostasis in disease pathogenesis. Since EVs can enter the systemic circulation and are easily detectable in patients' biological fluids, they have generated broad interest both as diagnostic and prognostic biomarkers and as valuable tools in understanding disease pathogenesis. Here, after a brief introduction on biogenesis and functions of EVs, we aim to investigate their role in neurodegenerative disorders, especially ALS. Specifically, we focus on the main findings supporting EV-mediated protein and RNA transmission in ALS in vitro and in vivo models. Then, we provide an overview of clinical applications of EVs, summarizing the most relevant studies able to detect EVs in blood and cerebrospinal fluid (CSF) of ALS patients, underlying their potential use in aiding diagnosis and prognosis. Finally, we explore the therapeutic applications of EVs in ALS, either as targets or as vehicles of proteins, nucleic acids and molecular drugs.

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Section: Evidence Of Prion-like Ev-mediated Misfolded Protein Propagamentioning

confidence: 63%

Section: Evidence Of Prion-like Ev-mediated Misfolded Protein Propagamentioning

confidence: 99%

Extracellular vesicles and amyotrophic lateral sclerosis: from misfolded protein vehicles to promising clinical biomarkers

Gagliardi

Bresolin

Comi

et al. 2020

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…Meanwhile, in terms of microglia, SOD1 secretion is known to be partially dependent on exosomes [88]. Activated N9 microglial cells were further unraveled to possess the 5 Oxidative Medicine and Cellular Longevity ability to secrete SOD1 via exosomes in vitro.…”

Section: Glial Exosomes In Alsmentioning

confidence: 99%

Central Nervous System Cell‐Derived Exosomes in Neurodegenerative Diseases

Tian

et al. 2021

Oxidative Medicine and Cellular Longevity

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Exosomes are a type of extracellular vesicles secreted by almost all kinds of mammalian cells that shuttle “cargo” from one cell to another, indicative of its role in cell-to-cell transportation. Interestingly, exosomes are known to undergo alterations or serve as a pathway in multiple diseases, including neurodegenerative diseases. In the central nervous system (CNS), exosomes originating from neurons or glia cells contribute to or inhibit the progression of CNS-related diseases in special ways. In lieu of this, the current study investigated the effect of CNS cell-derived exosomes on different neurodegenerative diseases.

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“…In addition, the team showed that brain astrocytes and neurons, but not microglia, were the main source of EVs (Silverman et al, 2019). Conversely, Massenzio et al (2018) demonstrated that microglial cells were capable of releasing SOD1 via exosomes. The study also showed that while intercellular accumulation of mutant SOD1 led to microglial activation and autophagy dysfunction, induction of autophagy through trehalose treatment significantly inhibited SOD1 accumulation and neurotoxicity through proteasome degradation (Massenzio et al, 2018).…”

Section: Excretion and Propagation Of Als-related Proteins Through Exosomesmentioning

confidence: 99%

“…Conversely, Massenzio et al (2018) demonstrated that microglial cells were capable of releasing SOD1 via exosomes. The study also showed that while intercellular accumulation of mutant SOD1 led to microglial activation and autophagy dysfunction, induction of autophagy through trehalose treatment significantly inhibited SOD1 accumulation and neurotoxicity through proteasome degradation (Massenzio et al, 2018). Overall, these studies help to support the prion-like transmission hypothesis that propagated protein misfolding may be responsible for the spatiotemporal progression of ALS (Ravits and La Spada, 2009;Polymenidou and Cleveland, 2011).…”

Section: Excretion and Propagation Of Als-related Proteins Through Exosomesmentioning

confidence: 99%

Exosomal Proteins and miRNAs as Mediators of Amyotrophic Lateral Sclerosis

Chen

Wen

et al. 2021

Front. Cell Dev. Biol.

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Recent advances in the neurobiology and neurogenerative diseases have attracted growing interest in exosomes and their ability to carry and propagate active biomolecules as a means to reprogram recipient cells. Alterations in exosomal protein content and nucleic acid profiles found in human biological fluids have been correlated with various diseases including amyotrophic lateral sclerosis (ALS). In ALS pathogenesis, these lipid-bound nanoscale vesicles have emerged as valuable candidates for diagnostic biomarkers. Moreover, their capacity to spread misfolded proteins and functional non-coding RNAs to interconnected neuronal cells make them putative mediators for the progressive motor degeneration found remarkably apparent in ALS. This review outlines current knowledge concerning the biogenesis, heterogeneity, and function of exosomes in the brain as well as a comprehensive probe of currently available literature on ALS-related exosomal proteins and microRNAs. Lastly, with the rapid development of employing nanoparticles for drug delivery, we explore the therapeutic potentials of exosomes as well as underlying limitations in current isolation and detection methodologies.

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Microglial overexpression of fALS-linked mutant SOD1 induces SOD1 processing impairment, activation and neurotoxicity and is counteracted by the autophagy inducer trehalose

Cited by 35 publications

References 117 publications

Extracellular vesicles and amyotrophic lateral sclerosis: from misfolded protein vehicles to promising clinical biomarkers

Extracellular vesicles and amyotrophic lateral sclerosis: from misfolded protein vehicles to promising clinical biomarkers

Central Nervous System Cell‐Derived Exosomes in Neurodegenerative Diseases

Exosomal Proteins and miRNAs as Mediators of Amyotrophic Lateral Sclerosis

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