Dataset Information

Distinct features of plasma extracellular vesicles in amyotrophic lateral sclerosis patients

ABSTRACT: Extracellular vesicles (EVs) are nanostructures that are used as sources of biomarkers. To better understand whether EVs could be exploited as diagnostic and prognostic biomarkers in Amyotrophic Lateral Sclerosis (ALS), we analyzed plasma-derived of ALS patients and relative healthy and diseased controls. Using the nickel-based isolation, a recently published EV purification method, we unmasked peculiar features in plasma EVs of ALS patients with a potential straightforward application in a clinical setting. We report that the number of particles is increased in the plasma of ALS patients and of two mouse models of ALS while the average diameter is decreased. Proteins like HSP90 and phosphorylated TDP-43 are differentially represented in ALS patients and mice compared to the controls. In terms of disease progression, the levels of phosphorylated TDP-43 and cyclophilin A, along with the EV size distribution discriminated fast and slow progressors of the diseases suggesting a new means for patient stratification. We exploited the EV size distribution with machine learning analysis that combining different EV parameters resulted in very high prediction rates for disease diagnosis and prognosis

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

DISEASE(S): Amyotrophic Lateral Sclerosis-parkinsonism/dementia Complex 1

SUBMITTER: Laura Brunelli

LAB HEAD: Roberta Pastorelli

PROVIDER: PXD020629 | Pride | 2021-09-09

REPOSITORIES: Pride

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Decoding distinctive features of plasma extracellular vesicles in amyotrophic lateral sclerosis.

Pasetto Laura L Callegaro Stefano S Corbelli Alessandro A Fiordaliso Fabio F Ferrara Deborah D Brunelli Laura L Sestito Giovanna G Pastorelli Roberta R Bianchi Elisa E Cretich Marina M Chiari Marcella M Potrich Cristina C Moglia Cristina C Corbo Massimo M Sorarù Gianni G Lunetta Christian C Calvo Andrea A Chiò Adriano A Mora Gabriele G Pennuto Maria M Quattrone Alessandro A Rinaldi Francesco F D'Agostino Vito Giuseppe VG Basso Manuela M Bonetto Valentina V

Molecular neurodegeneration 20210810 1

<h4>Background</h4>Amyotrophic lateral sclerosis (ALS) is a multifactorial, multisystem motor neuron disease for which currently there is no effective treatment. There is an urgent need to identify biomarkers to tackle the disease's complexity and help in early diagnosis, prognosis, and therapy. Extracellular vesicles (EVs) are nanostructures released by any cell type into body fluids. Their biophysical and biochemical characteristics vary with the parent cell's physiological and pathological st ...[more]

PMID: 34376243

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Project description:Aims: Loss of nuclear TDP-43 characterises sporadic and most familial forms of amyotrophic lateral sclerosis (ALS). TDP-43 (encoded by TARDBP) has multiple roles in RNA processing. We aimed to determine whether 1) RNA splicing dysregulation is present in lower motor neurons in ALS and in a motor neuron-like cell model, and 2) TARDBP mutations (mtTARDBP) are associated with aberrant RNA splicing using patient-derived fibroblasts. Methods: Affymetrix exon arrays were used to study mRNA expression and splicing in lower motor neurons obtained by laser capture microdissection of autopsy tissue from individuals with sporadic ALS and TDP-43 proteinopathy. Findings were confirmed by qRT-PCR and in NSC34 motor neuronal cells following shRNA-mediated TDP-43 depletion. Exon arrays and immunohistochemistry were used to study mRNA splicing and TDP-43 expression in fibroblasts from patients with mtTARDBP-associated, sporadic and mutant SOD1-associated ALS. Results: We found altered expression of spliceosome components in motor neurons and widespread aberrations of mRNA splicing that specifically affected genes involved in ribonucleotide binding. This was confirmed in TDP-43 depleted NSC34 cells. Fibroblasts with mtTARDBP showed loss of nuclear TDP-43 protein and demonstrated similar changes in splicing and gene expression, that were not present in fibroblasts from patients with sporadic or SOD1-related ALS. Conclusion: Loss of nuclear TDP-43 is associated with RNA processing abnormalities in ALS motor neurons, patient-derived cells with mtTARDBP, and following artificial TDP-43 depletion, suggesting that splicing dysregulation directly contributes to disease pathogenesis. Key functional pathways affected include those central to RNA metabolism. RNA was extracted from fibroblasts grown from neurologically healthy controls (n=6) and 3 groups of patients with ALS: 1) sporadic cases (n=6); 2) cases due to mutations of SOD1 (n=4); 3) cases due to mutations of TARDBP (n=3). The three ALS groups were compared to the controls.

Project description:Aims: Loss of nuclear TDP-43 characterises sporadic and most familial forms of amyotrophic lateral sclerosis (ALS). TDP-43 (encoded by TARDBP) has multiple roles in RNA processing. We aimed to determine whether 1) RNA splicing dysregulation is present in lower motor neurons in ALS and in a motor neuron-like cell model, and 2) TARDBP mutations (mtTARDBP) are associated with aberrant RNA splicing using patient-derived fibroblasts. Methods: Affymetrix exon arrays were used to study mRNA expression and splicing in lower motor neurons obtained by laser capture microdissection of autopsy tissue from individuals with sporadic ALS and TDP-43 proteinopathy. Findings were confirmed by qRT-PCR and in NSC34 motor neuronal cells following shRNA-mediated TDP-43 depletion. Exon arrays and immunohistochemistry were used to study mRNA splicing and TDP-43 expression in fibroblasts from patients with mtTARDBP-associated, sporadic and mutant SOD1-associated ALS. Results: We found altered expression of spliceosome components in motor neurons and widespread aberrations of mRNA splicing that specifically affected genes involved in ribonucleotide binding. This was confirmed in TDP-43 depleted NSC34 cells. Fibroblasts with mtTARDBP showed loss of nuclear TDP-43 protein and demonstrated similar changes in splicing and gene expression, that were not present in fibroblasts from patients with sporadic or SOD1-related ALS. Conclusion: Loss of nuclear TDP-43 is associated with RNA processing abnormalities in ALS motor neurons, patient-derived cells with mtTARDBP, and following artificial TDP-43 depletion, suggesting that splicing dysregulation directly contributes to disease pathogenesis. Key functional pathways affected include those central to RNA metabolism. RNA was extracted from lower motor neurons obtained by laser capture microdissection from autopsy material from neurologically healthy controls (n=6) and cases of sporadic ALS (n=3) and ALS due to C9ORF72 mutations (n=3).

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