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Cited by 14Amyotrophic Lateral Sclerosis ResearchNeurogenetic and Muscular Disorders ResearchMuscle Physiology and Disorders

Intrathecal Injection of the Secretome from ALS Motor Neurons Regulated for miR-124 Expression Prevents Disease Outcomes in SOD1-G93A Mice

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Barbosa, Marta, Santos, Marta, de Sousa, Nídia, Duarte-Silva, Sara, Vaz, Ana Rita, Salgado, António J., Brites, Dora·2022·Biomedicines
DOI 10.3390/biomedicines10092120PMC PMC9496075
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Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with short life expectancy and no effective therapy. We previously identified upregulated miR-124 in NSC-34-motor neurons (MNs) expressing human SOD1-G93A (mSOD1) and established its implication in mSOD1 MN degeneration and glial cell activation. When anti-miR-124-treated mSOD1 MN (preconditioned) secretome was incubated in spinal cord organotypic cultures from symptomatic mSOD1 mice, the dysregulated homeostatic balance was circumvented. To decipher the therapeutic potential of such preconditioned secretome, we intrathecally injected it in mSOD1 mice at the early stage of the disease (12-week-old). Preconditioned secretome prevented motor impairment and was effective in counteracting muscle atrophy, glial reactivity/dysfunction, and the neurodegeneration of the symptomatic mSOD1 mice. Deficits in corticospinal function and gait abnormalities were precluded, and the loss of gastrocnemius muscle fiber area was avoided. At the molecular level, the preconditioned secretome enhanced NeuN mRNA/protein expression levels and the PSD-95/TREM2/IL-10/arginase 1/MBP/PLP genes, thus avoiding the neuronal/glial cell dysregulation that characterizes ALS mice. It also prevented upregulated GFAP/Cx43/S100B/vimentin and inflammatory-associated miRNAs, specifically miR-146a/miR-155/miR-21, which are displayed by symptomatic animals. Collectively, our study highlights the intrathecal administration of the secretome from anti-miR-124-treated mSOD1 MNs as a therapeutic strategy for halting/delaying disease progression in an ALS mouse model.

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  • miRNAs can be released by cells as free species directly into their secretome or selectively enriched in exosomes (diameter <150 nm) that, when internalized by target cells, affect their biological functions.

    “In general, miRNAs can be released by cells as free species directly into their secretome or selectively enriched in small extracellular vesicles (exosomes, diameter size <150 nm) that, when internalized by target cells, affect their biological functions [38,39,40,41].”

    From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [41]

    The Introduction (page not provided) says miRNAs can be released into the secretome as free species or encapsulated in small extracellular vesicles and internalized by neighbouring cells. The Discussion (page not provided) describes miR-124 carried to recipient microglial cells and altering their behaviour. Our copy does not establish selective enrichment in exosomes or the stated diameter of <150 nm. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Barbosa, M., Santos, M., de Sousa, N., Duarte-Silva, S., Vaz, A. R., Salgado, A. J., & Brites, D.
Affiliations
  • University of Lisbon (PT)
  • School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, 4710-057 Braga, Portugal
  • Laboratório Associado ICVS 3B's (PT)
Corresponding author
Brites, Dora
ORCID
Venue
Biomedicines
Publisher
MDPI AG
Published
2022-08-29
Volume
10
Issue
9
Pages
2120
ISSN
2227-9059 (ISSN-L)
DOI
10.3390/biomedicines10092120
PMC
PMC9496075
OpenAlex
W4293528066
Cited by
14
References
7
Citations by year
2026: 5 · 2025: 3 · 2024: 5 · 2022: 1
FWCI
1.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomedicines (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by-nc-nd)
Funders
  • Santa Casa da Misericórdia de Lisboa (ELA-2015-002, PTDC/MED-NEU/31395/2017, UIDB/UIDP/04138/2020, UID/DTP/04138/2019-2020, LISBOA-01-0145-FEDER-031395, HR21-00931, SFRH/BD/129586/2017, PPBI-POCI-01-0145-FEDER-022122)
  • Fundação para a Ciência e a Tecnologia (FCT) (ELA-2015-002, PTDC/MED-NEU/31395/2017, UIDB/UIDP/04138/2020, UID/DTP/04138/2019-2020, LISBOA-01-0145-FEDER-031395, HR21-00931, SFRH/BD/129586/2017, PPBI-POCI-01-0145-FEDER-022122)
  • Programa Operacional Regional de Lisboa (ELA-2015-002, PTDC/MED-NEU/31395/2017, UIDB/UIDP/04138/2020, UID/DTP/04138/2019-2020, LISBOA-01-0145-FEDER-031395, HR21-00931, SFRH/BD/129586/2017, PPBI-POCI-01-0145-FEDER-022122)
  • La Caixa Foundation (ELA-2015-002, PTDC/MED-NEU/31395/2017, UIDB/UIDP/04138/2020, UID/DTP/04138/2019-2020, LISBOA-01-0145-FEDER-031395, HR21-00931, SFRH/BD/129586/2017, PPBI-POCI-01-0145-FEDER-022122)
  • individual fellowship from FCT (ELA-2015-002, PTDC/MED-NEU/31395/2017, UIDB/UIDP/04138/2020, UID/DTP/04138/2019-2020, LISBOA-01-0145-FEDER-031395, HR21-00931, SFRH/BD/129586/2017, PPBI-POCI-01-0145-FEDER-022122)
  • ICVS Scientific Microscopy Platform (ELA-2015-002, PTDC/MED-NEU/31395/2017, UIDB/UIDP/04138/2020, UID/DTP/04138/2019-2020, LISBOA-01-0145-FEDER-031395, HR21-00931, SFRH/BD/129586/2017, PPBI-POCI-01-0145-FEDER-022122)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Keywords
amyotrophic lateral sclerosis, SOD1 G93A mice, miR-124, intrathecal administration, motor neuron degeneration, glial activation, neuroinflammation, muscle atrophy, neurodegeneration

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