LRRK2 kinase-mediated accumulation of lysosome-associated phospho-Rabs in tauopathies and synucleinopathies

Oct 23, 2025Acta neuropathologica

Build-up of modified proteins linked to cell recycling caused by LRRK2 enzyme in diseases with tau and alpha-synuclein buildup

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Abstract

pS106-Rab12 levels are increased in Alzheimer's disease and Lewy body disease.

mutations are linked to abnormal phosphorylation of , which may contribute to neurodegenerative conditions.
Phosphorylated Rab12 is found in , suggesting a role in lysosomal stress during early stages of pathology.
Increased pS106-Rab12 is associated with the presence of pathological tau in Alzheimer's disease and Lewy body disease.
In a mouse model, pS106-Rab12 accumulates in granulovacuolar degeneration bodies as tau deposition progresses with age.
While pT73-Rab10 is elevated in Alzheimer's disease and Lewy body disease, it does not co-localize with tau or α-synuclein inclusions.

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Parkinson's disease (PD) pathogenic mutations in leucine-rich repeat kinase 2 () 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 (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.

Key numbers

10×

Increase in pS106-Rab12

pS106-Rab12 levels in DLB cases with Braak tangle stage >3 vs. controls

5×

Elevated pT73-Rab10

pT73-Rab10 levels in DLB cases with Braak tangle stage >3 vs. controls

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LRRK2 kinase-mediated accumulation of lysosome-associated phospho-Rabs in tauopathies and synucleinopathies

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