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Loss of Proteostasis and Early-Onset Neurodegeneration in Down Syndrome: From Mechanisms to Interventions
Tramutola A, Lanzillotta C, Di Domenico F, Barone E, Perluigi M.. Antioxidants (Basel, Switzerland), 2026-04-21
Topic: Brain proteins, microglia and lab models
Down syndrome (DS), caused by trisomy 21, is the most prevalent genetic condition associated with accelerated aging and near-universal development of early-onset Alzheimer's disease (AD). Beyond gene-dosage imbalance, trisomy 21 induces widespread transcriptional, metabolic, and proteomic remodeling that establishes a chronic state of proteotoxic and oxidative stress from early development. Increasing evidence identifies DS as a disorder of proteostasis network failure, in which sustained translational pressure, redox disequilibrium, and degradation pathway insufficiency progressively erode cellular resilience. In the DS brain, persistent endoplasmic reticulum stress with PERK-dominant signaling, mitochondrial dysfunction characterized by oxidative phosphorylation deficits and excessive reactive oxygen species production, and impaired antioxidant responses create a highly vulnerable intracellular environment. Concomitantly, degradation systems become compromised: proteasomal catalytic activity declines, ubiquitin-dependent signaling is remodeled, and chronic mTOR hyperactivation suppresses autophagic and mitophagic flux. The coordinated impairment of the ubiquitin-proteasome system and autophagy establish a feed-forward cycle of proteotoxic accumulation and redox amplification. Within this framework, Alzheimer-like neuropathology in DS emerges not solely from amyloid precursor protein triplication but as the late manifestation of decades-long proteostasis exhaustion. Therapeutic strategies aimed at restoring global proteostasis and redox balance may therefore represent a more effective systems-level approach to mitigating neurodegeneration in DS.
Key findings
- Down syndrome (DS), caused by trisomy 21, is the most prevalent genetic condition associated with accelerated aging and near-universal development of early-onset Alzheimer's disease (AD).
Why it matters
This review proposes that Down syndrome involves a failure of the proteostasis network that contributes to early-onset Alzheimer's disease. It discusses mechanisms from published evidence and does not report a tested treatment, cure or prevention.
Study details
- Evidence strengthLow
How this study scored 39/100
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.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Antioxidants (Basel, Switzerland)) |
| Journal's citation record | 2 / 4 | Antioxidants: journal h-index 208 (OpenAlex, 2026-10-29) |
| 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 | 1 / 7 | Cited 2 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 4 / 6 | Cited 12.8× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 2 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Marzia Perluigi: h-index 63 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Sapienza University of Rome: institution h-index 1,145 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 42072161) |
| Free to read | 2 / 2 | Free to read |
| Total | 39 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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. Check the citation against the original before you use it.
APA 7th
Tramutola, A., Lanzillotta, C., Di Domenico, F., Barone, E., & Perluigi, M. (2026). Loss of Proteostasis and Early-Onset Neurodegeneration in Down Syndrome: From Mechanisms to Interventions. Antioxidants (Basel, Switzerland). https://doi.org/10.3390/antiox15040520
Vancouver
Tramutola A, Lanzillotta C, Di Domenico F, Barone E, Perluigi M. Loss of Proteostasis and Early-Onset Neurodegeneration in Down Syndrome: From Mechanisms to Interventions. Antioxidants (Basel, Switzerland). 2026. doi:10.3390/antiox15040520. PMID: 42072161.
BibTeX
@article{tramutola2026-42072161,
author = {Tramutola, A. and Lanzillotta, C. and Di Domenico, F. and Barone, E. and Perluigi, M.},
title = {{Loss of Proteostasis and Early-Onset Neurodegeneration in Down Syndrome: From Mechanisms to Interventions}},
journal = {Antioxidants (Basel, Switzerland)},
year = {2026},
doi = {10.3390/antiox15040520},
pmid = {42072161},
url = {https://doi.org/10.3390/antiox15040520}
}
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