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Cited by 96Amyotrophic Lateral Sclerosis ResearchTraumatic Brain Injury ResearchAlzheimer's disease research and treatments

Traumatic injury induces stress granule formation and enhances motor dysfunctions in ALS/FTD models

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Anderson, Eric N, Gochenaur, Lauren, Singh, Aditi, Grant, Rogan, Patel, Krishani, Watkins, Simon, Wu, Jane Y, Pandey, Udai Bhan·2018·Human Molecular Genetics
DOI 10.1093/hmg/ddy047PMC PMC6455923
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Abstract

Traumatic brain injury (TBI) has been predicted to be a predisposing factor for amyotrophic lateral sclerosis (ALS) and other neurological disorders. Despite the importance of TBI in ALS progression, the underlying cellular and molecular mechanisms are still an enigma. Here, we examined the contribution of TBI as an extrinsic factor and investigated whether TBI influences the susceptibility of developing neurodegenerative symptoms. To evaluate the effects of TBI in vivo, we applied mild to severe trauma to Drosophila and found that TBI leads to the induction of stress granules (SGs) in the brain. The degree of SGs induction directly correlates with the level of trauma. Furthermore, we observed that the level of mortality is directly proportional to the number of traumatic hits. Interestingly, trauma-induced SGs are ubiquitin, p62 and TDP-43 positive, and persistently remain over time suggesting that SGs might be aggregates and exert toxicity in our fly models. Intriguingly, TBI on animals expressing ALS-linked genes increased mortality and locomotion dysfunction suggesting that mild trauma might aggravate neurodegenerative symptoms associated with ALS. Furthermore, we found elevated levels of high molecular weight ubiquitinated proteins and p62 in animals expressing ALS-causing genes with TBI, suggesting that TBI may lead to the defects in protein degradation pathways. Finally, we observed that genetic and pharmacological induction of autophagy enhanced the clearance of SGs and promoted survival of flies in vivo. Together, our study demonstrates that trauma can induce SG formation in vivo and might enhance neurodegenerative phenotypes in the fly models of ALS.

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Cited by

Sorted by citations

Authors
Anderson, E. N., Gochenaur, L., Singh, A., Grant, R., Patel, K., Watkins, S., Wu, J. Y., & Pandey, U. B.
Affiliations
  • Children's Hospital of Pittsburgh (US)
  • University of Pittsburgh (US)
  • University of Pittsburgh Medical Center (US)
  • Northwestern University (US)
Corresponding author
Pandey, Udai Bhan
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2018-02-08
Volume
27
Issue
8
Pages
1366-1381
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddy047
PMC
PMC6455923
OpenAlex
W2792571530
Cited by
96
References
9
Citations by year
2026: 3 · 2025: 11 · 2024: 9 · 2023: 13 · 2022: 14 · 2021: 14 · 2020: 14 · 2019: 16 · 2018: 2
FWCI
7.81
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/about_us/legal/notices (vor)
Locations
  • Human Molecular Genetics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (NS081303, NS094921, NS100055, NS101661 and NS098379)
  • Muscular Dystrophy Association
  • Robert Packard Center
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
traumatic brain injury, stress granules, amyotrophic lateral sclerosis, frontotemporal dementia, Drosophila, motor impairment, TDP-43, p62, ubiquitin, autophagy, protein degradation, neurodegeneration, locomotion
MeSH terms
Brain Injuries, Traumatic, Amyotrophic Lateral Sclerosis, Animals, Autophagy, Brain, Carrier Proteins, Cytoplasmic Granules, Disease Models, Animal, DNA-Binding Proteins, Drosophila melanogaster, Humans, Locomotion, Longevity, Neurons, Protein Processing, Post-Translational, Trauma Severity Indices, Ubiquitin, Drosophila Proteins, Animals, Genetically Modified, Transcription Factor TFIID, TATA-Binding Protein Associated Factors, Ubiquitination, Frontotemporal Dementia

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