Pathogenic LRRK2 mutations, through increased kinase activity, produce enlarged lysosomes with reduced degradative capacity and increase ATP13A2 expression
Abstract
Lysosomal dysfunction plays a central role in the pathogenesis of several neurodegenerative disorders, including Parkinson's disease (PD). Several genes linked to genetic forms of PD, including leucine-rich repeat kinase 2 (LRRK2), functionally converge on the lysosomal system. While mutations in LRRK2 are commonly associated with autosomal-dominant PD, the physiological and pathological functions of this kinase remain poorly understood. Here, we demonstrate that LRRK2 regulates lysosome size, number and function in astrocytes, which endogenously express high levels of LRRK2. Expression of LRRK2 G2019S, the most common pathological mutation, produces enlarged lysosomes and diminishes the lysosomal capacity of these cells. Enlarged lysosomes appears to be a common phenotype associated with pathogenic LRRK2 mutations, as we also observed this effect in cells expressing other LRRK2 mutations; R1441C or Y1699C. The lysosomal defects associated with these mutations are dependent on both the catalytic activity of the kinase and autophosphorylation of LRRK2 at serine 1292. Further, we demonstrate that blocking LRRK2's kinase activity, with the potent and selective inhibitor PF-06447475, rescues the observed defects in lysosomal morphology and function. The present study also establishes that G2019S mutation leads to a reduction in lysosomal pH and increased expression of the lysosomal ATPase ATP13A2, a gene linked to a parkinsonian syndrome (Kufor-Rakeb syndrome), in brain samples from mouse and human LRRK2 G2019S carriers. Together, these results demonstrate that PD-associated LRRK2 mutations perturb lysosome function in a kinase-dependent manner, highlighting the therapeutic promise of LRRK2 kinase inhibitors in the treatment of PD.
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Lysosomal clustering is associated with lysosomal impairment.
“a phenotype previously observed in association with lysosomal impairment41,42”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [41]
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A toxic gain-of-function mechanism in C9orf72 ALS impairs the autophagy-lysosome pathway in neurons
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Pajarillo, E. A. B., Rizor, A., Lee, J., Aschner, M., & Lee, E.-S. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.11.017 · Cited by 39 · see citing works
Taking out the garbage: cathepsin D and calcineurin in neurodegeneration
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D’Souza, T., & Rajkumar, A. P. (2019) · Acta Neuropsychiatrica · doi:10.1017/neu.2019.28 · Cited by 37 · see citing works
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Mabrouk, O. S., Chen, S., Edwards, A., Yang, M., Hirst, W. D., & Graham, D. L. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00526 · Cited by 35 · see citing works
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- Authors
- Henry, A. G., Aghamohammadzadeh, S., Samaroo, H., Chen, Y., Mou, K., Needle, E., & Hirst, W. D.
- Affiliations
- Pfizer (United States) (US)
- Corresponding author
- Hirst, Warren D.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-08-06
- Volume
- 24
- Issue
- 21
- Pages
- 6013-6028
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2100867992
- Cited by
- 235
- References
- 90
- Citations by year
- 2026: 19 · 2025: 25 · 2024: 21 · 2023: 24 · 2022: 24 · 2021: 28 · 2020: 32 · 2019: 16 · 2018: 20 · 2017: 15 · 2016: 8 · 2015: 2
- FWCI
- 10.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of California, Davis
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- LRRK2, Parkinson's disease, lysosomal dysfunction, LRRK2 kinase activity, LRRK2 G2019S mutation, autophosphorylation, ATP13A2, lysosomal pH, astrocytes, Kufor-Rakeb syndrome, LRRK2 inhibitors
- MeSH terms
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Adenosine Triphosphatases, Animals, Astrocytes, Brain, Cells, Cultured, Proton-Translocating ATPases, Humans, Hydrogen-Ion Concentration, Lysosomes, Membrane Proteins, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Parkinson Disease, Phenotype, Phosphorylation, Up-Regulation, Protein Serine-Threonine Kinases, Mice
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