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Synaptic vesicle endocytosis deficits underlie cognitive dysfunction in mouse models of GBA-linked Parkinson’s disease and dementia with Lewy bodies
D. J. Vidyadhara, David C. Bäckström, Risha Chakraborty, Jiapeng Ruan, Jae-Min Park, Pramod Kumar Mistry, Sreeganga S. Chandra. Nature Communications, 2025-09-26
Topic: Brain proteins, microglia and lab models
GBA is the major risk gene for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), two common α-synucleinopathies with cognitive deficits. Here we investigate the role of mutant GBA in cognitive decline by utilizing Gba (L444P) mutant, SNCA transgenic (tg), and Gba-SNCA double mutant mice. Notably, Gba mutant mice show cognitive decline but lack PD-like motor deficits or α-synuclein pathology. Conversely, SNCA tg mice display age-related motor deficits, without cognitive abnormalities. Gba-SNCA mice exhibit both cognitive decline and exacerbated motor deficits, accompanied by greater cortical phospho-α-synuclein pathology, especially in layer 5 neurons. Single-nucleus RNA sequencing of the cortex uncovered synaptic vesicle (SV) endocytosis pathway defects in excitatory neurons of Gba mutant and Gba-SNCA mice, via downregulation of genes regulating SV cycle and synapse assembly. Immunohistochemistry and electron microscopy validate these findings. Our results indicate that Gba mutations, while exacerbating pre-existing α-synuclein aggregation and PD-like motor deficits, contribute to cognitive deficits through α-synuclein-independent mechanisms, involving dysfunction in SV endocytosis. GBA, a major gene for Parkinson’s disease and dementia with Lewy bodies, is associated with increased risk of developing dementia. Here, we demonstrate that GBA mutations in mice contribute to cognitive deficits through α-synuclein-independent mechanisms that impact synaptic vesicle endocytosis.
Key findings
- Immunohistochemistry and electron microscopy validate these findings.
- Our results indicate that Gba mutations, while exacerbating pre-existing α-synuclein aggregation and PD-like motor deficits, contribute to cognitive deficits through α-synuclein-independent mechanisms, involving dysfunction in SV endocytosis.
- GBA, a major gene for Parkinson’s disease and dementia with Lewy bodies, is associated with increased risk of developing dementia.
Why it matters
In mouse models, this study found that Gba mutations contribute to cognitive deficits through α-synuclein-independent mechanisms involving dysfunction in synaptic vesicle endocytosis. These are animal findings, so they are early and preliminary and do not yet show a treatment for people.
Study details
- Evidence strengthLow
How this study scored 46/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Nature Communications) |
| Journal's citation record | 4 / 4 | Nature Communications: journal h-index 747 (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 | 4 / 5 | 2025 — within 3 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 “mouse”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 12 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 4.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 6.8× 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 | 1 / 4 | Cited 12 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Sreeganga S. Chandra: h-index 28 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Yale University: institution h-index 1,927 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41006254) |
| Free to read | 2 / 2 | Free to read |
| Total | 46 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1038/s41467-025-63444-9
- PubMed: 41006254
- Original source →
- Free full text: Nature Communications →
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. The record names 7 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Vidyadhara, D. J., Bäckström, D. C., Chakraborty, R., Ruan, J., Park, J.-M., Mistry, P. K., et al. (2025). Synaptic vesicle endocytosis deficits underlie cognitive dysfunction in mouse models of GBA-linked Parkinson’s disease and dementia with Lewy bodies. Nature Communications. https://doi.org/10.1038/s41467-025-63444-9
Vancouver
Vidyadhara DJ, Bäckström DC, Chakraborty R, Ruan J, Park J.-M, Mistry PK, et al. Synaptic vesicle endocytosis deficits underlie cognitive dysfunction in mouse models of GBA-linked Parkinson’s disease and dementia with Lewy bodies. Nature Communications. 2025. doi:10.1038/s41467-025-63444-9. PMID: 41006254.
BibTeX
@article{vidyadhara2025-41006254,
author = {Vidyadhara, D. J. and Bäckström, David C. and Chakraborty, Risha and Ruan, Jiapeng and Park, Jae-Min and Mistry, Pramod Kumar and Chandra, Sreeganga S.},
title = {{Synaptic vesicle endocytosis deficits underlie cognitive dysfunction in mouse models of GBA-linked Parkinson’s disease and dementia with Lewy bodies}},
journal = {Nature Communications},
year = {2025},
doi = {10.1038/s41467-025-63444-9},
pmid = {41006254},
url = {https://doi.org/10.1038/s41467-025-63444-9}
}
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here.