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LRRK2 kinase-mediated accumulation of lysosome-associated phospho-Rabs in tauopathies and synucleinopathies
Silas A Buck, Tuyana Malankhanova, Samuel Strader, Eileen B Ma, Sarah Yim, Harrison W Pratt, John Ervin, Edward B Lee et al.. Acta neuropathologica, 2025-10-23
Topic: Disease mechanisms in lab and animal studies
Parkinson's disease (PD) pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with endolysosomal dysfunction across cell types, and carriers of LRRK2 mutations variably present with phosphorylated tau and α-synuclein deposits in post-mortem analysis. LRRK2 mutations increase the phosphorylation of Rab substrates including Rab12 and Rab10. Rab12 and Rab10 are expressed in neuronal and non-neuronal cells with localization to membranes in the endolysosomal compartment, and lysosomal stress activates LRRK2 phosphorylation of Rabs. In this study, using antibodies directed to the LRRK2-mediated phosphorylation sites on Rab12 at amino acid Ser106 (pS106-Rab12) and Rab10 at amino acid Thr73 (pT73-Rab10), we test whether aberrant LRRK2 phosphorylation is associated with tau and/or α-synuclein pathology across clinically distinct neurodegenerative diseases. Analysis of brain tissue lysates and immunohistochemistry of pathology-susceptible brain regions demonstrate that pS106-Rab12 levels are increased in Alzheimer's disease (AD) and Lewy body disease (LBD), including PD with and without G2019S LRRK2 mutation. At early pathological stages, phosphorylated Rab12 localizes to granulovacuolar degeneration bodies (GVBs), which are thought to be active lysosomal-like structures, in neurons. pS106-Rab12-positive GVBs accumulate with pathological tau across brain tissues in AD and LBD, and in G2019S LRRK2 mutation carriers. In a mouse model of tauopathy, pS106-Rab12 localizes to GVBs during early tau deposition in an age-dependent manner. While GVBs are largely absent in neurons with mature protein pathology, subsets of both tau and α-synuclein inclusions appear to incorporate pS106-Rab12 at later pathological stages. Further, pS106-Rab12 labels GVBs in neurons and shows co-pathology with tau inclusions in primary tauopathies including Pick's disease, progressive supranuclear palsy, and corticobasal degeneration. Finally, pT73-Rab10 is elevated and localizes to GVBs, but not tau and α-synuclein inclusions, in AD and LBD, including G2019S LRRK2 mutation carriers. These results implicate LRRK2 kinase activity and Rab phosphorylation in endolysosomal dysfunction in tau- and α-synuclein-associated neurodegenerative diseases.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Buck, S. A., Malankhanova, T., Strader, S., Ma, E. B., Yim, S., Pratt, H. W., et al. (2025). LRRK2 kinase-mediated accumulation of lysosome-associated phospho-Rabs in tauopathies and synucleinopathies. Acta neuropathologica. https://doi.org/10.1007/s00401-025-02951-x
Vancouver
Buck SA, Malankhanova T, Strader S, Ma EB, Yim S, Pratt HW, et al. LRRK2 kinase-mediated accumulation of lysosome-associated phospho-Rabs in tauopathies and synucleinopathies. Acta neuropathologica. 2025. doi:10.1007/s00401-025-02951-x. PMID: 41128923.
BibTeX
@article{buck2025-41128923,
author = {Buck, Silas A and Malankhanova, Tuyana and Strader, Samuel and Ma, Eileen B and Yim, Sarah and Pratt, Harrison W and Ervin, John and Lee, Edward B and others},
title = {{LRRK2 kinase-mediated accumulation of lysosome-associated phospho-Rabs in tauopathies and synucleinopathies}},
journal = {Acta neuropathologica},
year = {2025},
doi = {10.1007/s00401-025-02951-x},
pmid = {41128923},
url = {https://doi.org/10.1007/s00401-025-02951-x}
}
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Key findings
- Parkinson's disease (PD) pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with endolysosomal dysfunction across cell types, and carriers of LRRK2 mutations variably present with phosphorylated tau and α-synuclein deposits in post-mortem analysis.
- In this study, using antibodies directed to the LRRK2-mediated phosphorylation sites on Rab12 at amino acid Ser106 (pS106-Rab12) and Rab10 at amino acid Thr73 (pT73-Rab10), we test whether aberrant LRRK2 phosphorylation is associated with tau and/or α-synuclein pathology across clinically distinct neurodegenerative diseases.
- These results implicate LRRK2 kinase activity and Rab phosphorylation in endolysosomal dysfunction in tau- and α-synuclein-associated neurodegenerative diseases.
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, studied in people and randomized / 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, multicenter collaboration and free to read, so those were left out: it earned 26 of the 56 points we could judge it on, which is 46 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Acta neuropathologica) |
| 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 | 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) |
| Randomized / blinded | 0 / 2 | No randomization 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 |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41128923) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 26 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 26 of the 56 points we could judge it on is 46 out of 100. |
| Total | 46 / 100 | — |
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