Abstract
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the deposition of misfolded proteins in the motor cortex and motor neurons. Although a multitude of ALS-associated mutated proteins have been identified, several have been linked to small extracellular vesicles such as exosomes involved in cell−cell communication. This study aims to determine the proteome of extracellular vesicles isolated from the motor cortex of ALS subjects and to identify novel ALS-associated deregulated proteins. Motor cortex extracellular vesicles (MCEVs) were isolated from human postmortem ALS (n = 10) and neurological control (NC, n = 5) motor cortex brain tissues and the MCEVs protein content subsequently underwent mass spectrometry analysis, allowing for a panel of ALS-associated proteins to be identified. This panel consists of 16 statistically significant differentially packaged proteins identified in the ALS MCEVs. This includes several upregulated RNA-binding proteins which were determined through pathway analysis to be associated with stress granule dynamics. The identification of these RNA-binding proteins in the ALS MCEVs suggests there may be a relationship between ALS-associated stress granules and ALS MCEV packaging, highlighting a potential role for small extracellular vesicles such as exosomes in the pathogenesis of ALS and as potential peripheral biomarkers for ALS.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease, characterized by the deposition of ubiquitinated, aggregated proteins in Lewy body-like hyaline or skein-like inclusions in the cytoplasm of upper and lower motor neurons [1,2,3]
We show expression of stress granule proteins STAU1 and DExH-Box Helicase 30 (DHX30) to be enhanced in ALS Motor cortex extracellular vesicles (MCEVs) compared to neurological controls (NC)
The results of this study demonstrated enrichment of ALS MCEVs with CTF TDP-43 and revealed
Summary
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease, characterized by the deposition of ubiquitinated, aggregated proteins in Lewy body-like hyaline or skein-like inclusions in the cytoplasm of upper and lower motor neurons [1,2,3]. Mutations in 126 genes have been implicated in ALS pathology including most recently OPTN (which encodes optineurin) and VCP (which encodes valosin-containing protein) [5,6]. Intronic repeats in Chromosome 9 open reading frame 72 (C9ORF72) and mutations in SOD1 (which encodes superoxide dismutase 1), TARDBP ALS pathogenesis can be caused by cellular stressors, which induce the generation of stress granules, a form of cytoplasmic ribonucleoprotein particles [12,13]. These granules arise from the aggregation of nontranslating mRNAs and their RNA-binding proteins, and permit the cell to conserve energy by decreasing the translation rates of most mRNAs, with the exception of stress-responsive
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
