Cited by 244Parkinson's Disease Mechanisms and TreatmentsAutophagy in Disease and TherapyLysosomal Storage Disorders Research

The DOI matches its Crossref record; 87 of the 90 references it cites were found in a registry or an index.

Pathogenic LRRK2 mutations, through increased kinase activity, produce enlarged lysosomes with reduced degradative capacity and increase ATP13A2 expression

Henry, Anastasia G., Aghamohammadzadeh, Soheil, Samaroo, Harry, Chen, Yi, Mou, Kewa, Needle, Elie, Hirst, Warren D.·2015·Human Molecular Genetics

DOI 10.1093/hmg/ddv314

Open this paper in CoChat — free account

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1093/hmg/ddv314

Cites

87 of 87 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

α-Synuclein in Lewy bodies
Spillantini, M. G., Schmidt, M. L., Lee, V. M.-Y., Trojanowski, J. Q., Jakes, R., & Goedert, M. (1997) · Nature · doi:10.1038/42166 · Cited by 8,382
An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875
Regulation mechanisms and signaling pathways of autophagy
He, C., & Klionsky, D. J. (2009) · Annual Review of Genetics · doi:10.1146/annurev-genet-102808-114910 · Cited by 3,609
Lysosomes: fusion and function
Luzio, J. P., Pryor, P. R., & Bright, N. A. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2217 · Cited by 1,807
Signals from the lysosome: a control centre for cellular clearance and energy metabolism
Settembre, C., Fraldi, A., Medina, D. L., & Ballabio, A. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3565 · Cited by 1,755
Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function
Saftig, P., & Klumperman, J. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2745 · Cited by 1,648
ENDOCYTOSIS AND MOLECULAR SORTING
Mellman, I. (1996) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.12.1.575 · Cited by 1,551
Lysosomes and autophagy in cell death control
Kroemer, G., & Jäättelä, M. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1738 · Cited by 1,322
Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity
West, A. B., Moore, D. J., Biskup, S., Bugayenko, A., Smith, W. W., Ross, C. A., Dawson, V. L., & Dawson, T. M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507360102 · Cited by 1,228
Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 Mutations
Lee, J.-H., Yu, W. H., Kumar, A., Lee, S., Mohan, P. S., Peterhoff, C. M., Wolfe, D. M., Martinez-Vicente, M., Massey, A. C., Sovak, G., et al. (2010) · Cell · doi:10.1016/j.cell.2010.05.008 · Cited by 1,212

Show all 90 references

Sorted by citations

Lysosomal membrane permeabilization and cell death
Wang, F., Gómez‐Sintes, R., & Boya, P. (2018) · Traffic · doi:10.1111/tra.12613 · Cited by 804
The Role of Astrocyte Dysfunction in Parkinson’s Disease Pathogenesis
Booth, H. D. E., Hirst, W. D., & Wade-Martins, R. (2017) · Trends in Neurosciences · doi:10.1016/j.tins.2017.04.001 · Cited by 633
Self-citation
Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease
Colacurcio, D. J., & Nixon, R. A. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.05.004 · Cited by 548
The genetics of Parkinson disease
Deng, H., Wang, P., & Jankovic, J. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2017.12.007 · Cited by 530
The different autophagy degradation pathways and neurodegeneration
Fleming, A., Bourdenx, M., Fujimaki, M., Karabiyik, C., Krause, G. J., Lopez, A., Martín‐Segura, A., Puri, C., Scrivo, A., Skidmore, J., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.01.017 · Cited by 500
The emerging mechanisms and functions of microautophagy
Wang, L., Klionsky, D. J., & Shen, H. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00529-z · Cited by 495
Microglia and astrocyte dysfunction in parkinson's disease
Kam, T., Hinkle, J. T., Dawson, T. M., & Dawson, V. L. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105028 · Cited by 420
α-Synuclein pathology in Parkinson’s disease and related α-synucleinopathies
Henderson, M. X., Trojanowski, J. Q., & Lee, V. M. ‐. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134316 · Cited by 301
Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson’s disease
Jennings, D. L., Huntwork, S., Henry, A. G., Sasaki, J. C., Meisner, R., Diaz, D., Solanoy, H. O., Wang, X., Negrou, E., Bondar, V. V., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abj2658 · Cited by 261
Self-citation
LRRK2 mediates tubulation and vesicle sorting from lysosomes
Bonet‐Ponce, L., Beilina, A. G., Williamson, C. D., Lindberg, E., Kluss, J. H., Sáez-Atiénzar, S., Landeck, N., Kumaran, R., Mamais, A., Bleck, C. K. E., et al. (2020) · Science Advances · doi:10.1126/sciadv.abb2454 · Cited by 252
Ischemia-induced upregulation of autophagy preludes dysfunctional lysosomal storage and associated synaptic impairments in neurons
Zhang, X., Wei, M., Fan, J., Yan, W., Zha, X., Song, H., Wan, R., Yin, Y., & Wang, W. (2020) · Autophagy · doi:10.1080/15548627.2020.1840796 · Cited by 230
Mitochondrial abnormalities in Parkinson's disease and Alzheimer's disease: can mitochondria be targeted therapeutically?
Macdonald, R., Barnes, K., Hastings, C., & Mortiboys, H. (2018) · Biochemical Society Transactions · doi:10.1042/bst20170501 · Cited by 223
LRRK2 links genetic and sporadic Parkinson's disease
Kluss, J. H., Mamais, A., & Cookson, M. R. (2019) · Biochemical Society Transactions · doi:10.1042/bst20180462 · Cited by 221
Probiotic Bacillus subtilis protects against α-synuclein aggregation in C. elegans
Goya, M. E., Xue, F., Sampedro-Torres-Quevedo, C., Arnaouteli, S., Riquelme-Dominguez, L., Romanowski, A., Brydon, J., Ball, K. L., Stanley-Wall, N. R., & Doitsidou, M. (2020) · Cell Reports · doi:10.1016/j.celrep.2019.12.078 · Cited by 205
Neuron-Astrocyte Interactions in Parkinson’s Disease
Miyazaki, I., & Asanuma, M. (2020) · Cells · doi:10.3390/cells9122623 · Cited by 186
G2019S-LRRK2 Expression Augments -Synuclein Sequestration into Inclusions in Neurons
Volpicelli‐Daley, L. A., Abdelmotilib, H., Liu, Z., Stoyka, L. E., Daher, J. P. L., Milnerwood, A. J., Unni, V. K., Hirst, W. D., Yue, Z., Zhao, H., et al. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.3642-15.2016 · Cited by 185
Self-citation
Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease
West, A. B. (2017) · Experimental Neurology · doi:10.1016/j.expneurol.2017.07.019 · Cited by 182
LRRK2 regulation of immune-pathways and inflammatory disease
Wallings, R. L., & Tansey, M. G. (2019) · Biochemical Society Transactions · doi:10.1042/bst20180463 · Cited by 181
Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain
Lin, G., Lee, P.-T., Chen, K., Mao, D., Tan, K. L., Zuo, Z., Lin, W., Wang, L., & Bellen, H. J. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.05.019 · Cited by 173
LRRK2 and idiopathic Parkinson’s disease
Rocha, E. M., Keeney, M. T., Maio, R. D., Miranda, B. R. D., & Greenamyre, J. T. (2022) · Trends in Neurosciences · doi:10.1016/j.tins.2021.12.002 · Cited by 173
Glial phagocytic clearance in Parkinson’s disease
Tremblay, M.-E., Cookson, M. R., & Civiero, L. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0314-8 · Cited by 152
Brain energy metabolism: Astrocytes in neurodegenerative diseases.
Chen, Z., Yuan, Z., Yang, S., Zhu, Y., Xue, M., Zhang, J., & Leng, L. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13982 · Cited by 153
Urinary proteome profiling for stratifying patients with familial Parkinson’s disease
Winter, S. V., Karayel, Ö., Strauss, M. T., Padmanabhan, S., Surface, M., Merchant, K., Alcalay, R. N., & Mann, M. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202013257 · Cited by 149
Endocytic membrane trafficking and neurodegenerative disease
Schreij, A. M. A., Fon, E. A., & McPherson, P. S. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2105-x · Cited by 160
RETRACTED ARTICLE: LRRK2 kinase regulates α-synuclein propagation via RAB35 phosphorylation
Bae, E.-J., Kim, D.-K., Kim, C., Mante, M., Adame, A., Rockenstein, E., Ulusoy, A., Klinkenberg, M., Jeong, G. R., Bae, J. R., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05958-z · Cited by 149
Retracted
Glial Contribution to Excitatory and Inhibitory Synapse Loss in Neurodegeneration
Henstridge, C. M., Tzioras, M., & Paolicelli, R. C. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00063 · Cited by 155
Lysosomal Dysfunction at the Centre of Parkinson’s Disease and Frontotemporal Dementia/Amyotrophic Lateral Sclerosis
Wallings, R. L., Humble, S. W., Ward, M. E., & Wade-Martins, R. (2019) · Trends in Neurosciences · doi:10.1016/j.tins.2019.10.002 · Cited by 153
Autophagy impairment in Parkinson’s disease
Karabiyik, C., Lee, M. J., & Rubinsztein, D. C. (2017) · Essays in Biochemistry · doi:10.1042/ebc20170023 · Cited by 141
“LRRK2: Autophagy and Lysosomal Activity”
Madureira, M., Connor‐Robson, N., & Wade‐Martins, R. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00498 · Cited by 143
Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble α-synuclein in neurons
Schapansky, J., Khasnavis, S., DeAndrade, M. P., Nardozzi, J. D., Falkson, S. R., Boyd, J. D., Sanderson, J. B., Bartels, T., Melrose, H. L., & LaVoie, M. J. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.12.005 · Cited by 137
Advances in elucidating the function of leucine-rich repeat protein kinase-2 in normal cells and Parkinson's disease
Taylor, M., & Alessi, D. R. (2020) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2020.01.001 · Cited by 141
LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease
Jennings, D. L., Huntwork, S., Vissers, M. F. J. M., Daryani, V. M., Diaz, D., Goo, M. S., Chen, J. J.-W., Maciuca, R. D., Fraser, K. B., Mabrouk, O. S., et al. (2023) · Movement Disorders · doi:10.1002/mds.29297 · Cited by 130
Self-citation
Sphingolipids in the Pathogenesis of Parkinson’s Disease and Parkinsonism
Lin, G., Wang, L., Marcogliese, P. C., & Bellen, H. J. (2018) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2018.11.003 · Cited by 132
Global and Regional Changes in Perivascular Space in Idiopathic and Familial Parkinson's Disease
Donahue, E. K., Murdos, A., Jakowec, M. W., Sheikh‐Bahaei, N., Toga, A. W., Petzinger, G. M., & Sepehrband, F. (2021) · Movement Disorders · doi:10.1002/mds.28473 · Cited by 124
Parkinson’s Disease–Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance
Streubel-Gallasch, L., Giusti, V., Sandre, M., Tessari, I., Plotegher, N., Giusto, E., Masato, A., Iovino, L., Battisti, I., Arrigoni, G., et al. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02327-8 · Cited by 100
Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases
Lo, C. H., & Zeng, J. (2023) · Translational Neurodegeneration · doi:10.1186/s40035-023-00362-0 · Cited by 117
Lysosome and Inflammatory Defects in GBA1‐Mutant Astrocytes Are Normalized by LRRK2 Inhibition
Sanyal, A., DeAndrade, M. P., Novis, H. S., Lin, S. C., Chang, J., Lengacher, N. A., Tomlinson, J. J., Tansey, M. G., & LaVoie, M. J. (2020) · Movement Disorders · doi:10.1002/mds.27994 · Cited by 111
LRRK2 and the Endolysosomal System in Parkinson’s Disease
Erb, M. L., & Moore, D. J. (2020) · Journal of Parkinson s Disease · doi:10.3233/jpd-202138 · Cited by 109
Innate Immunity: A Common Denominator between Neurodegenerative and Neuropsychiatric Diseases
Novellino, F., Saccà, V., Donato, A., Zaffino, P., Spadea, M. F., Vismara, M. F. M., Arcidiacono, B., Malara, N., Presta, I., & Donato, G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21031115 · Cited by 107
LRRK2 and Parkinson's disease: from genetics to targeted therapy
Sosero, Y. L., & Gan‐Or, Z. (2023) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.51776 · Cited by 97
A new hypothesis for Parkinson’s disease pathogenesis: GTPase-p38 MAPK signaling and autophagy as convergence points of etiology and genomics
Obergasteiger, J., Frapporti, G., Pramstaller, P. P., Hicks, A. A., & Volta, M. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0273-5 · Cited by 97
Glucocerebrosidase and Parkinson Disease: Molecular, Clinical, and Therapeutic Implications
Balestrino, R., & Schapira, A. H. V. (2018) · The Neuroscientist · doi:10.1177/1073858417748875 · Cited by 105
Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes
Guo, J. L., Braun, D., Fitzgerald, G. A., Hsieh, Y.-T., Rougé, L., Litvinchuk, A., Steffek, M., Propson, N. E., Heffner, C. M., Discenza, C., et al. (2025) · Cell · doi:10.1016/j.cell.2024.10.027 · Cited by 91
“41,42 Therefore, acute lipofuscin induction by CE(20:4)-ApoE3/4 is sufﬁcient to cause lysosomal defects.”
LRRK2 and α-Synuclein: Distinct or Synergistic Players in Parkinson’s Disease?
O’Hara, D. M., Pawar, G. N., Kalia, S. K., & Kalia, L. V. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00577 · Cited by 89
Autophagy in Synucleinopathy: The Overwhelmed and Defective Machinery
Arotçarena, M.-L., Teil, M., & Dehay, B. (2019) · Cells · doi:10.3390/cells8060565 · Cited by 91
Astrocyte dysfunction in Parkinson's disease: from the perspectives of transmitted α-synuclein and genetic modulation
Wang, C., Yang, T., Liang, M., Xie, J., & Song, N. (2021) · Translational Neurodegeneration · doi:10.1186/s40035-021-00265-y · Cited by 90
Elevated LRRK2 autophosphorylation in brain-derived and peripheral exosomes in LRRK2 mutation carriers
Wang, S., Liu, Z., Ye, T., Mabrouk, O. S., Maltbie, T., Aasly, J. O., & West, A. B. (2017) · Acta Neuropathologica Communications · doi:10.1186/s40478-017-0492-y · Cited by 83
mTOR independent regulation of macroautophagy by Leucine Rich Repeat Kinase 2 via Beclin-1
Manzoni, C., Mamais, A., Roosen, D. A., Dihanich, S., Soutar, M. P. M., Plun‐Favreau, H., Bandopadhyay, R., Hardy, J., Tooze, S. A., Cookson, M., et al. (2016) · Scientific Reports · doi:10.1038/srep35106 · Cited by 89
Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia
Mamais, A., Kluss, J. H., Bonet‐Ponce, L., Landeck, N., Langston, R. G., Smith, N., Beilina, A. G., Kaganovich, A., Ghosh, M. C., Pellegrini, L., et al. (2021) · PLoS Biology · doi:10.1371/journal.pbio.3001480 · Cited by 81
The G2019S variant of leucine-rich repeat kinase 2 (LRRK2) alters endolysosomal trafficking by impairing the function of the GTPase RAB8A
Rivero-Ríos, P., Romo-Lozano, M., Madero-Pérez, J., Thomas, A. P., Biosa, A., Greggio, E., & Hilfiker, S. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.005008 · Cited by 83
LRRK2 at the Interface Between Peripheral and Central Immune Function in Parkinson’s
Wallings, R. L., Herrick, M. K., & Tansey, M. G. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00443 · Cited by 80
Two-pore channels and disease
Patel, S., & Kilpatrick, B. S. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2018.05.004 · Cited by 77
LRRK2 recruitment, activity, and function in organelles
Bonet‐Ponce, L., & Cookson, M. (2021) · FEBS Journal · doi:10.1111/febs.16099 · Cited by 82
Autophagy in Astrocytes and its Implications in Neurodegeneration
Sung, K., & Jiménez-Sánchez, M. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.12.041 · Cited by 78
LRRK2 suppresses lysosome degradative activity in macrophages and microglia through MiT-TFE transcription factor inhibition
Yadavalli, N., & Ferguson, S. M. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2303789120 · Cited by 74
Impact of Type II LRRK2 inhibitors on signaling and mitophagy
Tasegian, A., Singh, F., Ganley, I. G., Reith, A. D., & Alessi, D. R. (2021) · Biochemical Journal · doi:10.1042/bcj20210375 · Cited by 79
LRRK2 Phosphorylation, More Than an Epiphenomenon
Marchand, A., Drouyer, M., Sarchione, A., Chartier‐Harlin, M., & Taymans, J. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00527 · Cited by 70
The Emerging Functions of LRRK2 and Rab GTPases in the Endolysosomal System
Kuwahara, T., & Iwatsubo, T. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00227 · Cited by 73
Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease
Smith, L. J., Lee, C., Menozzi, E., & Schapira, A. H. V. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.971252 · Cited by 67
Alteration of endosomal trafficking is associated with early-onset parkinsonism caused by SYNJ1 mutations
Fasano, D., Parisi, S., Pierantoni, G. M., Rosa, A. D., Picillo, M., Amodio, G., Pellecchia, M. T., Barone, P., Moltedo, O., Bonifati, V., et al. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-0410-7 · Cited by 68
Neuroinflammation in Parkinson’s Disease: Triggers, Mechanisms, and Immunotherapies
Wang, T., Shi, C., Luo, H., Zheng, H., Fan, L., Tang, M., Su, Y., Yang, J., Mao, C., & Xu, Y. (2021) · The Neuroscientist · doi:10.1177/1073858421991066 · Cited by 69
Blocking IL-6 signaling prevents astrocyte-induced neurodegeneration in an iPSC-based model of Parkinson’s disease
Pons‐Espinal, M., Blasco-Agell, L., Fernández‐Carasa, I., Andrés‐Benito, P., di Domenico, A., Richaud‐Patín, Y., Baruffi, V., Marruecos, L., Espinosa, L., Garrido, A., et al. (2024) · JCI Insight · doi:10.1172/jci.insight.163359 · Cited by 69
The V-ATPase–ATG16L1 axis recruits LRRK2 to facilitate the lysosomal stress response
Eguchi, T., Sakurai, M., Wang, Y., Saito, C., Yoshii, G., Wileman, T. E., Mizushima, N., Kuwahara, T., & Iwatsubo, T. (2023) · The Journal of Cell Biology · doi:10.1083/jcb.202302067 · Cited by 59
Additional rare variant analysis in Parkinson’s disease cases with and without known pathogenic mutations: Evidence for oligogenic inheritance
Lubbe, S. J., Escott-Price, V., Gibbs, J. R., Nalls, M. A., Bras, J., Price, T. R., Nicolas, A., Jansen, I. E., Mok, K. Y., Pittman, A. M., et al. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw348 · Cited by 61
The LRRK2–macroautophagy axis and its relevance to Parkinson's disease
Manzoni, C. (2017) · Biochemical Society Transactions · doi:10.1042/bst20160265 · Cited by 57
Call to action to properly utilize electron microscopy to measure organelles to monitor disease
Neikirk, K., Lopez, E. G., Marshall, A. G., Alghanem, A. F., Krystofiak, E., Kula, B., Smith, N., Shao, J., Katti, P., & Hinton, A. O., Jr. (2023) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2023.151365 · Cited by 67
LRRK2 and the Immune System
Dzamko, N. L. (2017) · Advances in neurobiology · doi:10.1007/978-3-319-49969-7_7 · Cited by 62
Deregulation of autophagy and vesicle trafficking in Parkinson’s disease
Sheehan, P., & Yue, Z. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2018.04.013 · Cited by 56
Kinase inhibition of G2019S-LRRK2 enhances autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions
Obergasteiger, J., Frapporti, G., Lamonaca, G., Pizzi, S., Picard, A., Lavdas, A. Α., Pischedda, F., Piccoli, G., Hilfiker, S., Lobbestael, E., et al. (2020) · Cell Death Discovery · doi:10.1038/s41420-020-0279-y · Cited by 56
Structural basis for Parkinson’s disease-linked LRRK2’s binding to microtubules
Snead, D. M., Matyszewski, M., Dickey, A. M., Lin, Y. X., Leschziner, A. E., & Reck-Peterson, S. L. (2022) · Nature Structural & Molecular Biology · doi:10.1038/s41594-022-00863-y · Cited by 54
Neurodegeneration cell per cell
Balusu, S., Praschberger, R., Lauwers, E., Strooper, B. D., & Verstreken, P. (2023) · Neuron · doi:10.1016/j.neuron.2023.01.016 · Cited by 53
TXNIP mediates high glucose-induced mitophagic flux and lysosome enlargement in human retinal pigment epithelial cells
Devi, T. S., Yumnamcha, T., Yao, F., Somayajulu, M., Kowluru, R. A., & Singh, L. P. (2019) · Biology Open · doi:10.1242/bio.038521 · Cited by 58
The Parkinson’s disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons
Jones-Tabah, J., He, K., Karpilovsky, N. C., Senkevich, K. A., Deyab, G., Pietrantonio, I., Goiran, T., Cousineau, Y., Nikanorova, D., Goldsmith, T., et al. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00779-9 · Cited by 53
Recent Developments in LRRK2-Targeted Therapy for Parkinson’s Disease
Zhao, Y., & Dzamko, N. L. (2019) · Drugs · doi:10.1007/s40265-019-01139-4 · Cited by 54
Fibrillar α-synuclein toxicity depends on functional lysosomes
Guiney, S. J., Adlard, P. A., Lei, P., Mawal, C., Bush, A. I., Finkelstein, D. I., & Ayton, S. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.013428 · Cited by 52
The role of glia in protein aggregation
Li, Q., & Haney, M. S. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105015 · Cited by 54
Reduced LRRK2 in association with retromer dysfunction in post-mortem brain tissue from LRRK2 mutation carriers
Zhao, Y., Perera, G., Takahashi-Fujigasaki, J., Mash, D. C., Vonsattel, J. P. G., Uchino, A., Hasegawa, K., Jeremy Nichols, R., Holton, J. L., Murayama, S., et al. (2018) · Brain · doi:10.1093/brain/awx344 · Cited by 49
Role of Astrocytes in Parkinson’s Disease Associated with Genetic Mutations and Neurotoxicants
Kim, S., Pajarillo, E. A. B., Nyarko‐Danquah, I., Aschner, M., & Lee, E.-S. (2023) · Cells · doi:10.3390/cells12040622 · Cited by 60
Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease
Marchetti, B. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101664 · Cited by 52
Understanding LRRK2 kinase activity in preclinical models and human subjects through quantitative analysis of LRRK2 and pT73 Rab10
Wang, X., Negrou, E., Maloney, M. T., Bondar, V. V., Andrews, S. V., Montalban, M., Llapashtica, C., Maciuca, R. D., Nguyen, H. N., Solanoy, H. O., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-91943-4 · Cited by 50
Self-citation
Modulation of the Interactions Between α-Synuclein and Lipid Membranes by Post-translational Modifications
Bell, R., & Vendruscolo, M. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.661117 · Cited by 52
LRRK2 Kinase Inhibition Rescues Deficits in Lysosome Function Due to Heterozygous GBA1 Expression in Human iPSC-Derived Neurons
Sanyal, A., Novis, H. S., Gasser, E., Lin, S. C., & LaVoie, M. J. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00442 · Cited by 50
LRRK2 activity does not dramatically alter α-synuclein pathology in primary neurons
Henderson, M. X., Peng, C., Trojanowski, J. Q., & Lee, V. M. ‐. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0550-0 · Cited by 46
LRRK2 kinase activity regulates GCase level and enzymatic activity differently depending on cell type in Parkinson’s disease
Kedariti, M., Frattini, E., Baden, P., Cogo, S., Civiero, L., Ziviani, E., Zilio, G., Bertoli, F., Aureli, M., Kaganovich, A., et al. (2022) · npj Parkinson s Disease · doi:10.1038/s41531-022-00354-3 · Cited by 45
Aging, cellular senescence and Parkinson's disease
Ma, Y., Erb, M. L., & Moore, D. J. (2025) · Journal of Parkinson s Disease · doi:10.1177/1877718x251316552 · Cited by 47
Sequential screening nominates the Parkinson's disease associated kinase LRRK2 as a regulator of Clathrin-mediated endocytosis
Heaton, G. R., Landeck, N., Mamais, A., Nalls, M. A., Nixon-Abell, J., Kumaran, R., Beilina, A., Pellegrini, L., Li, Y., Harvey, K., et al. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104948 · Cited by 43
α-Synuclein Overexpression Induces Lysosomal Dysfunction and Autophagy Impairment in Human Neuroblastoma SH-SY5Y
Nascimento, A. C., Erustes, A. G., Reckziegel, P., Bincoletto, C., Ureshino, R. P., Pereira, G. J. S., & Smaili, S. S. (2020) · Neurochemical Research · doi:10.1007/s11064-020-03126-8 · Cited by 46
A Perspective on the Link between Mitochondria-Associated Membranes (MAMs) and Lipid Droplets Metabolism in Neurodegenerative Diseases
Fernandes, T., Domingues, M. R., Moreira, P. I., & Pereira, C. (2023) · Biology · doi:10.3390/biology12030414 · Cited by 45
Glial Nrf2 signaling mediates the neuroprotection exerted by Gastrodia elata Blume in Lrrk2-G2019S Parkinson’s disease
Lin, Y., Lin, C.-H., Ho, E.-P., Ke, Y.-C., Petridi, S., Elliott, C. J. H., Sheen, L., & Chien, C.-T. (2021) · eLife · doi:10.7554/elife.73753 · Cited by 47
A toxic gain-of-function mechanism in C9orf72 ALS impairs the autophagy-lysosome pathway in neurons
Beckers, J., Tharkeshwar, A. K., Fumagalli, L., Contardo, M., Schoor, E. V., Fazal, R., Thal, D. R., Chandran, S., Mancuso, R., Bosch, L. V. D., et al. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01648-0 · Cited by 44
The role of posttranslational modifications of α-synuclein and LRRK2 in Parkinson's disease: Potential contributions of environmental factors
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 44
Taking out the garbage: cathepsin D and calcineurin in neurodegeneration
Büttner, S., Aufschnaiter, A., & Kohler, V. (2017) · Neural Regeneration Research · doi:10.4103/1673-5374.219031 · Cited by 38
Systematic review of genetic variants associated with cognitive impairment and depressive symptoms in Parkinson’s disease
D’Souza, T., & Rajkumar, A. P. (2019) · Acta Neuropsychiatrica · doi:10.1017/neu.2019.28 · Cited by 37
Glial cells in Parkinson´s disease: protective or deleterious?
Domingues, A. V., Pereira, I. M., Vilaça-Faria, H., Salgado, A. J., Rodrigues, A. J., & Teixeira, F. G. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03584-x · Cited by 38
Lysosomal acidification impairment in astrocyte-mediated neuroinflammation
Zeng, J., Indajang, J., Pitt, D., & Lo, C. H. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03410-w · Cited by 44
Glial Nrf2 signaling mediates the neuroprotection exerted by Gastrodia elata Blume in Lrrk2-G2019S Parkinson's disease.
Lin, Y., Lin, C., Ho, E.-P., Ke, Y., Petridi, S., Elliott, C. J. H., Sheen, L., & Chien, C. (2021) · White Rose Research Online (University of Leeds, The University of Sheffield, University of York) · doi:10.17863/cam.79311 · Cited by 36
Quantitative Measurements of LRRK2 in Human Cerebrospinal Fluid Demonstrates Increased Levels in G2019S Patients
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
Self-citation
LRRK2 kinase inhibition protects against Parkinson's disease-associated environmental toxicants
Ilieva, N. M., Hoffman, E. K., Ghalib, M., Greenamyre, J. T., & Miranda, B. R. D. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106522 · Cited by 32
A Cleaning Crew: The Pursuit of Autophagy in Parkinson’s Disease
Parekh, P., Sharma, N., Gadepalli, A., Shahane, A., Sharma, M., & Khairnar, A. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00244 · Cited by 34
68 and FX2149 Attenuate Mutant LRRK2-R1441C-Induced Neural Transport Impairment
Thomas, J. M., Li, T., Yang, W., Xue, F., Fishman, P. S., & Smith, W. W. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2016.00337 · Cited by 36

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.
ORCID: Henry, Anastasia G.
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
DOI: 10.1093/hmg/ddv314
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 › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Health Sciences › Medicine › Genetics (clinical) › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Pathogenic LRRK2 mutations, through increased kinase activity, produce enlarged lysosomes with reduced degradative capacity and increase ATP13A2 expression

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks