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Cited by 44Amyotrophic Lateral Sclerosis ResearchPluripotent Stem Cells ResearchAlzheimer's disease research and treatments

Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology

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de Majo, Martina, Koontz, Mark, Marsan, Elise, Salinas, Nir, Ramsey, Arren, Kuo, Yien-Ming, Seo, Kyounghee, Li, Huinan +10 more·2023·Stem Cell Reports
DOI 10.1016/j.stemcr.2023.01.012PMC PMC10031303

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Abstract

Loss of function (LoF) of TAR-DNA binding protein 43 (TDP-43) and mis-localization, together with TDP-43-positive and hyperphosphorylated inclusions, are found in post-mortem tissue of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those carrying LoF variants in the progranulin gene ( GRN ). Modeling TDP-43 pathology has been challenging in vivo and in vitro . We present a three-dimensional induced pluripotent stem cell (iPSC)-derived paradigm—mature brain organoids (mbOrg)—composed of cortical-like-astrocytes (iA) and neurons. When devoid of GRN , mbOrgs spontaneously recapitulate TDP-43 mis-localization, hyperphosphorylation, and LoF phenotypes. Mixing and matching genotypes in mbOrgs showed that GRN −/− iA are drivers for TDP-43 pathology. Finally, we rescued TDP-43 LoF by adding exogenous progranulin, demonstrating a link between TDP-43 LoF and progranulin expression. In conclusion, we present an iPSC-derived platform that shows striking features of human TDP-43 proteinopathy and provides a tool for the mechanistic modeling of TDP-43 pathology and patient-tailored therapeutic screening for FTD and ALS.

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  • NLK is an essential kinase - homozygous Nlk deletion results in death in utero or postnatally, depending on the mouse strain.

    “NLK is an essential kinase — homozygous Nlk deletion results in death in utero or postnatally, depending on the mouse strain (57, 58).”

    From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [57]

    The Introduction and Results discuss GRN loss of function in human brain organoids, not NLK deletion in mice. Searches for NLK, Nlk deletion, and strain-dependent embryonic or postnatal death found no passage addressing the claim in our copy. (LLM, conf=0.76)

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Authors
de Majo, M., Koontz, M., Marsan, E., Salinas, N., Ramsey, A., Kuo, Y.-M., Seo, K., Li, H., Dräger, N., Leng, K., Gonzales, S. L., Kurnellas, M., Miyaoka, Y., Klim, J. R., Kampmann, M., Ward, M. E., Huang, E. J., & Ullian, E. M.
Affiliations
  • University of California, San Francisco (US)
  • Alector (United States) (US)
  • Gladstone Institutes (US)
  • Broad Institute (US)
  • National Institutes of Health (US)
Corresponding author
Ullian, Erik M.
ORCID
Venue
Stem Cell Reports
Publisher
Elsevier BV
Published
2023-03
Volume
18
Issue
3
Pages
706-719
ISSN
2213-6711 (ISSN-L)
DOI
10.1016/j.stemcr.2023.01.012
PMC
PMC10031303
OpenAlex
W4321613216
Cited by
44
References
12
Citations by year
2026: 5 · 2025: 18 · 2024: 15 · 2023: 6
FWCI
7.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Stem Cell Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • Research to Prevent Blindness
  • National Institutes of Health
  • University of California, San Francisco (/ NEI P30 EY002162)
  • National Institute on Aging (2 P30 EY02162-39, R01 AG057528, AG062422-01, R03AG063157, R44NS124457)
  • National Eye Institute (P30 EY002162)
  • American Federation for Aging Research
  • Glenn Foundation for Medical Research
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
TDP-43, progranulin, astrocytes, brain organoids, amyotrophic lateral sclerosis, frontotemporal dementia, TDP-43 mislocalization, iPSC-derived neurons, disease modeling, therapeutic screening
MeSH terms
Progranulins, Granulins, Amyotrophic Lateral Sclerosis, Astrocytes, Brain, DNA-Binding Proteins, Humans, Mutation, Frontotemporal Dementia

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