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Longitudinal single-cell transcriptional profiling identifies dynamic neurodegenerative mechanisms in Christianson Syndrome rat
Riaz HA, Soman SK, Devlin JF, Kumar G, Lee Y, Morrow EM.. bioRxiv, 2026-10-20
Topic: Inflammation, microglia and astrocytes
Endolysosomal dysfunction is a central feature of many neurodegenerative disorders. Loss-of-function mutations in the endosomal Na+/H+ exchanger NHE6 cause lysosomal dysfunction and the early-onset neurodegenerative disorder Christianson syndrome (CS). CS shares pathological features with more common neurodegenerative diseases; however, the extent of mechanistic overlap remains unclear. Using single-nucleus RNA sequencing across the lifespan in a CS rat model, we define the temporal progression of disease at single-cell resolution in the hippocampus. Neurons exhibit early transcriptional signatures of mitochondrial dysfunction. We investigated mitochondrial function in vitro and ex vivo and discover progressive defects in mitochondrial quality control and bioenergetics in NHE6-null tissue. Furthermore, both transcriptomic and proteomic analyses reveal robust activation of innate immunity, including cGAS-STING signaling which localizes to microglia. Therefore, in CS rat brain, early neuronal endosomal and mitochondrial impairments are followed by pronounced microglial and astrocytic activation, as well as age-dependent decline in oligodendrocyte myelinating capacity. Cross species comparison reveals substantial overlap between single-cell analyses in CS rat and in human postmortem Alzheimers disease hippocampus. Together, our findings define the cellular trajectories of neurodegeneration in CS, and identify convergent endolysosomal, mitochondrial, and inflammatory mechanisms that support a broader role for endolysosomal dysfunction in Alzheimers disease pathogenesis.
Key findings
- Together, our findings define the cellular trajectories of neurodegeneration in CS, and identify convergent endolysosomal, mitochondrial, and inflammatory mechanisms that support a broader role for endolysosomal dysfunction in Alzheimers disease pathogenesis.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it. We have no data on 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 and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| 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 | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| 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 | Laboratory or animal study (title names “rat”) — scores zero |
| 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 | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Riaz, H. A., Soman, S. K., Devlin, J. F., Kumar, G., Lee, Y., & Morrow, E. M. (2026). Longitudinal single-cell transcriptional profiling identifies dynamic neurodegenerative mechanisms in Christianson Syndrome rat. bioRxiv. https://doi.org/10.64898/2026.10.14.756427
Vancouver
Riaz HA, Soman SK, Devlin JF, Kumar G, Lee Y, Morrow EM. Longitudinal single-cell transcriptional profiling identifies dynamic neurodegenerative mechanisms in Christianson Syndrome rat. bioRxiv. 2026. doi:10.64898/2026.10.14.756427.
BibTeX
@article{riaz2026-1fe6b0f9,
author = {Riaz, H. A. and Soman, S. K. and Devlin, J. F. and Kumar, G. and Lee, Y. and Morrow, E. M.},
title = {{Longitudinal single-cell transcriptional profiling identifies dynamic neurodegenerative mechanisms in Christianson Syndrome rat}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.10.14.756427},
url = {https://doi.org/10.64898/2026.10.14.756427}
}