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Abundant non-inclusion α-synuclein pathology in Lewy body-negative LRRK2-mutant cases
Nanna Møller Jensen, Zagorka Vitic, Mia R. Antorini, Tobias Bruun Viftrup, Laura Parkkinen, Poul Henning Jensen. Acta Neuropathologica, 2025-05-02
Topic: Brain proteins, microglia and lab models
Lewy body diseases are common neurodegenerative diseases, including Parkinson's disease (PD) and dementia with Lewy bodies, which lead to both motor and non-motor symptoms. They are neuropathologically characterized by loss of neuromelanized neurons in the substantia nigra pars compacta and α-synuclein-immunopositive inclusions (Lewy bodies) in several types of neurons in the brain. A fraction of monogenic PD cases, however, represent a conundrum, as they can present with clinical Lewy body disease but do not have Lewy bodies upon neuropathological examination. For LRRK2, the presence or absence of Lewy bodies is not related to any specific mutation in the gene and different clinical presentation and neuropathology can be present even in the same family. Here, we present the first evidence of widespread α-synuclein accumulation detected with proximity ligation assay (PLA) using the MJFR14-6-4-2 antibody in six Lewy body-negative LRRK2 cases and compare the levels with five patients with neuropathologically verified Lewy body disease and six healthy controls. We show that non-inclusion aggregated α-synuclein in the form of particulate PLA signal is dominant in the LRRK2 cases, while both Lewy-like and particulate PLA signal is found in late-stage Lewy body disease. Furthermore, LRRK2 cases displayed prominent particulate PLA signal in pontocerebellar tracts and inferior olivary nuclei in the brainstem, which was not seen in idiopathic Lewy body disease cases. These results suggest that Lewy-body negative LRRK2-related PD is not associated with a lack of α-synuclein aggregation in neurons but rather a deficiency in the formation of inclusions.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Jensen, N. M., Vitic, Z., Antorini, M. R., Viftrup, T. B., Parkkinen, L., & Jensen, P. H. (2025). Abundant non-inclusion α-synuclein pathology in Lewy body-negative LRRK2-mutant cases. Acta Neuropathologica. https://doi.org/10.1007/s00401-025-02871-w
Vancouver
Jensen NM, Vitic Z, Antorini MR, Viftrup TB, Parkkinen L, Jensen PH. Abundant non-inclusion α-synuclein pathology in Lewy body-negative LRRK2-mutant cases. Acta Neuropathologica. 2025. doi:10.1007/s00401-025-02871-w. PMID: 40314782.
BibTeX
@article{jensen2025-40314782,
author = {Jensen, Nanna Møller and Vitic, Zagorka and Antorini, Mia R. and Viftrup, Tobias Bruun and Parkkinen, Laura and Jensen, Poul Henning},
title = {{Abundant non-inclusion α-synuclein pathology in Lewy body-negative LRRK2-mutant cases}},
journal = {Acta Neuropathologica},
year = {2025},
doi = {10.1007/s00401-025-02871-w},
pmid = {40314782},
url = {https://doi.org/10.1007/s00401-025-02871-w}
}
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Key findings
- These results suggest that Lewy-body negative LRRK2-related PD is not associated with a lack of α-synuclein aggregation in neurons but rather a deficiency in the formation of inclusions.
Why it matters
This postmortem study found widespread non-inclusion alpha-synuclein accumulation in Lewy body-negative LRRK2-mutant cases, suggesting these cases have a deficiency in forming inclusions rather than a lack of aggregation. It concerns Lewy body disease and Parkinson's disease, not Alzheimer's disease, and tests no treatment, cure or prevention.
Study details
- Evidence strengthLow
How this study scored 52/100
Published in a leading specialty 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 | 9 / 10 | Tier 2 — leading specialty journal (Acta Neuropathologica) |
| Journal's citation record | 3 / 4 | Acta Neuropathologica: journal h-index 287 (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 | 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 | 4 / 7 | Cited 48 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 16.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 5 / 6 | Cited 26.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 2 other studies in this library |
| Still being cited | 2 / 4 | Cited 47 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Poul Henning Jensen: h-index 60 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Oxford: institution h-index 2,205 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40314782) |
| Free to read | 2 / 2 | Free to read |
| Total | 52 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1007/s00401-025-02871-w
- PubMed: 40314782
- Original source →
- Free full text: Acta Neuropathologica →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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