Progranulin deficiency-induced lysosomal dysfunction drives maladaptive myeloid cell states through the MITF/TFE transcription factors
Leon Tejwani, Catherine M Heffner, Christopher Balak, Lukas L Skuja, David Tatarakis, Anil Rana, Seungyoon B Yu, Gabriel A Fitzgerald et al.. Immunity, 2026-08-03
Topic: Inflammation, microglia and astrocytes
Lysosomal dysfunction in myeloid cells is increasingly implicated in neurodegenerative diseases. To examine the interplay between lysosomal health and cellular state, we performed multi-omic profiling of myeloid cells from brains of aged mice lacking progranulin (Grn-/- mice), a lysosomal protein linked to neurodegeneration. Single-cell RNA sequencing identified a microglial subpopulation defined by GPNMB expression, which displays hallmarks of lysosomal stress, including altered lysosomal protein expression, lipofuscinosis, and metabolic and lipid dysregulation. Epigenetic profiling of Grn-/- microglia revealed an enrichment of MITF/TFE transcription factor motifs at active enhancers, and deletion of these factors reversed the Grn-/--specific myeloid cell transcriptional signature. Diverse lysosomal perturbations drove a common transcriptional and functional signature, with conditions that induce lysosomal deacidification closely phenocopying progranulin deficiency. Finally, compensatory GPNMB induction in Grn-/- myeloid cells promoted lysosomal acidification, and loss of myeloid cell GPNMB exacerbated neurotoxicity. Our findings link lysosomal health with epigenetic, transcriptional, and functional myeloid cell states associated with neurodegeneration.
Key findings
- Epigenetic profiling of Grn-/- microglia revealed an enrichment of MITF/TFE transcription factor motifs at active enhancers, and deletion of these factors reversed the Grn-/--specific myeloid cell transcriptional signature.
- Our findings link lysosomal health with epigenetic, transcriptional, and functional myeloid cell states associated with neurodegeneration.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Evidence strengthLow
How this study scored 45/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 25 of the 56 points we could judge it on, which is 45 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Immunity) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 42546695) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 25 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 25 of the 56 points we could judge it on is 45 out of 100. |
| Total | 45 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Free copy unknown: no free-copy check has an answer for this record yet. That does not mean it is paywalled.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Tejwani, L., Heffner, C. M., Balak, C., Skuja, L. L., Tatarakis, D., Rana, A., et al. (2026). Progranulin deficiency-induced lysosomal dysfunction drives maladaptive myeloid cell states through the MITF/TFE transcription factors. Immunity. https://doi.org/10.1016/j.immuni.2026.07.009
Vancouver
Tejwani L, Heffner CM, Balak C, Skuja LL, Tatarakis D, Rana A, et al. Progranulin deficiency-induced lysosomal dysfunction drives maladaptive myeloid cell states through the MITF/TFE transcription factors. Immunity. 2026. doi:10.1016/j.immuni.2026.07.009. PMID: 42546695.
BibTeX
@article{tejwani2026-42546695,
author = {Tejwani, Leon and Heffner, Catherine M and Balak, Christopher and Skuja, Lukas L and Tatarakis, David and Rana, Anil and Yu, Seungyoon B and Fitzgerald, Gabriel A and others},
title = {{Progranulin deficiency-induced lysosomal dysfunction drives maladaptive myeloid cell states through the MITF/TFE transcription factors}},
journal = {Immunity},
year = {2026},
doi = {10.1016/j.immuni.2026.07.009},
pmid = {42546695},
url = {https://doi.org/10.1016/j.immuni.2026.07.009}
}