Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation
Open accessAbstract
Subpopulations of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNpc) display a differential vulnerability to loss in Parkinson's disease (PD); however, it is not clear why these subsets are preferentially selected in PD-associated neurodegeneration. In rodent SNpc, DA neurons can be divided into two subpopulations based on the expression of aldehyde dehydrogenase 1 (ALDH1A1). Here, we have shown that, in α-synuclein transgenic mice, a murine model of PD-related disease, DA neurodegeneration occurs mainly in a dorsomedial ALDH1A1-negative subpopulation that is also prone to cytotoxic aggregation of α-synuclein. Notably, the topographic ALDH1A1 pattern observed in α-synuclein transgenic mice was conserved in human SNpc. Postmortem evaluation of brains of patients with PD revealed a severe reduction of ALDH1A1 expression and neurodegeneration in the ventral ALDH1A1-positive DA subpopulations. ALDH1A1 expression was also suppressed in α-synuclein transgenic mice. Deletion of Aldh1a1 exacerbated α-synuclein-mediated DA neurodegeneration and α-synuclein aggregation, whereas Aldh1a1-null and control DA neurons were comparably susceptible to 1-methyl-4-phenylpyridinium-, glutamate-, or camptothecin-induced cell death. ALDH1A1 overexpression appeared to preferentially protect against α-synuclein-mediated DA neurodegeneration but did not rescue α-synuclein-induced loss of cortical neurons. Together, our findings suggest that ALDH1A1 protects subpopulations of SNpc DA neurons by preventing the accumulation of dopamine aldehyde intermediates and formation of cytotoxic α-synuclein oligomers.
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
Cites
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?
Aldh1a1+ dopamine neurons of the substantia nigra pars compacta are selectively decreased in a mouse model of Parkinson's disease and in human brains affected by the disease.
“In addition, Aldh1a1+ DA neurons of the SNc are selectively decreased in a mouse model of PD [13], as well as in human brains affected by the disease [25].”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [25]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The Mouse Brain in Stereotaxic Coordinates
Paxinos, G. (2001) · Cited by 12,859 · see citing works
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 · see citing works
Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease
Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., et al. (1997) · Science · doi:10.1126/science.276.5321.2045 · Cited by 8,240 · see citing works
α-Synuclein Locus Triplication Causes Parkinson's Disease
Singleton, A. B., Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J., Hulihan, M., Peuralinna, T., Dutra, A., Nussbaum, R., et al. (2003) · Science · doi:10.1126/science.1090278 · Cited by 4,383 · see citing works
AGEING AND PARKINSON'S DISEASE: SUBSTANTIA NIGRA REGIONAL SELECTIVITY
FEARNLEY, J. M., & LEES, A. J. (1991) · Brain · doi:10.1093/brain/114.5.2283 · Cited by 3,529 · see citing works
Genome-wide association study reveals genetic risk underlying Parkinson's disease
Simón‐Sánchez, J., Schulte, C., Brás, J., Sharma, M., Gibbs, J. R., Berg, D., Paisán‐Ruiz, C., Lichtner, P., Scholz, S. W., Hernandez, D. G., et al. (2009) · Nature Genetics · doi:10.1038/ng.487 · Cited by 1,916 · see citing works
The substantia nigra of the human brain
Damier, P., Hirsch, É. C., Agid, Y., & Graybiel, A. M. (1999) · Brain · doi:10.1093/brain/122.8.1437 · Cited by 1,772 · see citing works
Control of memory formation through regulated expression of a CaMKII transgene
Mayford, M., Bach, M. E., Huang, Y.-Y., Wang, L., Hawkins, R. D., & Kandel, E. R. (1996) · Science · doi:10.1126/science.274.5293.1678 · Cited by 1,550 · see citing works
Jeurgen, K., Assheuer, J., & Paxinos, G. (1997) · Medical Entomology and Zoology · Cited by 1,403 · see citing works
Satake, W., Nakabayashi, Y., Mizuta, I., Hirota, Y., Ito, C., Kubo, M., Kawaguchi, T., Tsunoda, T., Watanabe, M., Takeda, A., et al. (2009) · Nature Genetics · doi:10.1038/ng.485 · Cited by 1,308 · see citing works
Kinetic Stabilization of the α-Synuclein Protofibril by a Dopamine-α-Synuclein Adduct
Conway, K. A., Rochet, J.-C., Bieganski, R. M., & Lansbury, P. T. (2001) · Science · doi:10.1126/science.1063522 · Cited by 1,127 · see citing works
Direct Observation of the Interconversion of Normal and Toxic Forms of α-Synuclein
Cremades, N., Cohen, S. I. A., Deas, E., Abramov, A. Y., Chen, A. Y., Orte, Á., Sandal, M., Clarke, R. W., Dunne, P., Aprile, F. A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.037 · Cited by 901 · see citing works
Reynolds, I., & Hastings, T. (1995) · The Journal of Neuroscience · doi:10.1523/jneurosci.15-05-03318.1995 · Cited by 777 · see citing works
Dopamine covalently modifies and functionally inactivates parkin
LaVoie, M. J., Ostaszewski, B. L., Weihofen, A., Schlossmacher, M. G., & Selkoe, D. J. (2005) · Nature Medicine · doi:10.1038/nm1314 · Cited by 722 · see citing works
Ouimet, C. C., Miller, P. E., Hemmings, H. C., Walaas, S. I., & Greengard, P. (1984) · Journal of Neuroscience · doi:10.1523/jneurosci.04-01-00111.1984 · Cited by 655 · see citing works
The substantia nigra of the human brain
Damier, P., Hirsch, É. C., Agid, Y., & Graybiel, A. M. (1999) · Brain · doi:10.1093/brain/122.8.1421 · Cited by 579 · see citing works
Lin, X. Z., Parisiadou, L., Gu, X., Wang, L., Shim, H., Sun, L., Xie, C., Long, C.-X., Yang, W.-J., Ding, J., et al. (2009) · Neuron · doi:10.1016/j.neuron.2009.11.006 · Cited by 513 · see citing works
Self-citationNeumann, M., Kahle, P. J., Giasson, B. I., Ozmen, L., Borroni, E., Spooren, W. P. J. M., Müller, V., Odoy, S., Fujiwara, H., Hasegawa, M., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15777 · Cited by 351 · see citing works
Neuronal vulnerability, pathogenesis, and Parkinson's disease
Sulzer, D. L., & Surmeier, D. J. (2012) · Movement Disorders · doi:10.1002/mds.25095 · Cited by 315 · see citing works
Morris, E. J., & Geller, H. M. (1996) · The Journal of Cell Biology · doi:10.1083/jcb.134.3.757 · Cited by 310 · see citing works
Calcium, ageing, and neuronal vulnerability in Parkinson's disease
Surmeier, D. J. (2007) · The Lancet Neurology · doi:10.1016/s1474-4422(07)70246-6 · Cited by 297 · see citing works
Aggregated α-Synuclein Mediates Dopaminergic Neurotoxicity In Vivo
Periquet, M., Fulga, T. A., Myllykangas, L., Schlossmacher, M. G., & Feany, M. Β. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.0285-07.2007 · Cited by 291 · see citing works
Marchitti, S. A., Deitrich, R. A., & Vasiliou, V. (2007) · Pharmacological Reviews · doi:10.1124/pr.59.2.1 · Cited by 282 · see citing works
High levels of a retinoic acid-generating dehydrogenase in the meso-telencephalic dopamine system.
McCaffery, P., & Dräger, U. C. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.16.7772 · Cited by 266 · see citing works
The Sun Health Research Institute Brain Donation Program: Description and Eexperience, 1987–2007
Beach, T., Sue, L., Walker, D., Roher, A., Lue, L., Vedders, L. J., Connor, D., Sabbagh, M., & Rogers, J. (2007) · Cell and Tissue Banking · doi:10.1007/s10561-008-9067-2 · Cited by 265 · see citing works
Aggregation of α-synuclein by DOPAL, the monoamine oxidase metabolite of dopamine
Burke, W. J., Kumar, V. B., Pandey, N., Panneton, W. M., Gan, Q., Franko, M. W., Odell, M., Li, S. W., Pan, Y., Chung, H. D., et al. (2007) · Acta Neuropathologica · doi:10.1007/s00401-007-0303-9 · Cited by 243 · see citing works
Calcium, Bioenergetics, and Neuronal Vulnerability in Parkinson's Disease
Surmeier, D. J., & Schumacker, P. T. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.r112.410530 · Cited by 233 · see citing works
Fan, X., Molotkov, A., Manabe, S.-I., Donmoyer, C. M., Deltour, L., Foglio, M. H., Cuenca, A. E., Blaner, W. S., Lipton, S. A., & Duester, G. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.13.4637-4648.2003 · Cited by 230 · see citing works
Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease
Fitzmaurice, A. G., Rhodes, S. L., Lulla, A., Murphy, N. P., Lam, H. A., O’Donnell, K. C., Barnhill, L. M., Casida, J. E., Cockburn, M., Sagasti, A., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1220399110 · Cited by 212 · see citing works
Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson's disease
Goldstein, D. S., Sullivan, P., Holmes, C. S., Miller, G. W., Alter, S. P., Strong, R., Mash, D. C., Kopin, I. J., & Sharabi, Y. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12345 · Cited by 206 · see citing works
Lin, X. Z., Parisiadou, L., Sgobio, C., Liu, G., Yu, J. H., Sun, L., Shim, H., Gu, X., Luo, J., Long, C., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1731-12.2012 · Cited by 188 · see citing works
Self-citationLam, H. A., Wu, N., Cely, I., Kelly, R. L., Hean, S., Richter, F., Magen, I., Cepeda, C., Ackerson, L. C., Walwyn, W., et al. (2011) · Journal of Neuroscience Research · doi:10.1002/jnr.22611 · Cited by 184 · see citing works
Galter, D., Buervenich, S., Belin, A. C., Anvret, M., & Olson, L. (2003) · Neurobiology of Disease · doi:10.1016/j.nbd.2003.09.001 · Cited by 175 · see citing works
Wey, M., Fernández, E., Martinez, P. A., Sullivan, P., Goldstein, D. S., & Strong, R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0031522 · Cited by 160 · see citing works
Retinoic acid counteracts developmental defects in the substantia nigra caused by Pitx3 deficiency
Jacobs, F. M. J., Smits, S. M., Noorlander, C. W., von Oerthel, L., van der Linden, A. J. A., Burbach, J. P. H., & Smidt, M. P. (2007) · Development · doi:10.1242/dev.02865 · Cited by 141 · see citing works
Kurz, A., Double, K. L., Lastres‐Becker, I., Tozzi, A., Tantucci, M., Bockhart, V., von Bonin, M., Garcı́a-Arencibia, M., Nuber, S., Schlaudraff, F., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011464 · Cited by 134 · see citing works
Levites, Y., Jansen, K. R., Smithson, L. A., Dakin, R. S., Holloway, V. M., Das, P., & Golde, T. E. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.2795-06.2006 · Cited by 128 · see citing works
Rees, J. N., Florang, V. R., Eckert, L. L., & Doorn, J. A. (2009) · Chemical Research in Toxicology · doi:10.1021/tx9000557 · Cited by 121 · see citing works
Chandran, J. S., Lin, X. Z., Zapata, A. G., Höke, A., Shimoji, M., Moore, S. O., Galloway, M. P., Laird, F. M., Wong, P. C., Price, D. L., et al. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2007.11.011 · Cited by 112 · see citing works
Self-citationSelective vulnerability of pigmented dopaminergic neurons in Parkinson's disease
Hirsch, É. C., Graybiel, A. M., & Agid, Y. (1989) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.1989.tb01778.x · Cited by 85 · see citing works
Zonisamide: its pharmacology, efficacy and safety in clinical trials
Brodie, M. J., Ben‐Menachem, E., Chouette, I., & Giorgi, L. (2012) · Acta Neurologica Scandinavica · doi:10.1111/ane.12016 · Cited by 74 · see citing works
Bilsland, J., Roy, S., Xanthoudakis, S., et al. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-07-02637.2002 · Cited by 74 · see citing works
Functional significance of aldehyde dehydrogenase ALDH1A1 to the nigrostriatal dopamine system
Anderson, D. W., Schray, R. C., Duester, G., & Schneider, J. S. (2011) · Brain Research · doi:10.1016/j.brainres.2011.06.051 · Cited by 65 · see citing works
α-synuclein and cytosolic dopamine: Stabilizing a bad situation
Sulzer, D. L. (2001) · Nature Medicine · doi:10.1038/nm1201-1280 · Cited by 61 · see citing works
Jinsmaa, Y., Florang, V. R., Rees, J., Vermeer, L. M. M., Eckert, L. L., Allen, E. M. G., Anderson, D. G., & Doorn, J. A. (2011) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2011.01.006 · Cited by 58 · see citing works
Luk, K. C., Rymar, V. V., van den Munckhof, P., Nicolau, S., Steriade, C., Bifsha, P., Drouin, J., & Sadikot, A. F. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12160 · Cited by 55 · see citing works
Pathogenesis of Parkinson's disease.
Schapira, A. H. V. (1997) · PubMed · Cited by 47 · see citing works
Kong, D., & Kotraiah, V. (2011) · Journal of Molecular Neuroscience · doi:10.1007/s12031-011-9688-y · Cited by 34 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. α-Synuclein in Lewy bod- ies. Nature. 1997;388(6645):839-840.
Cited by
Sorted by citations
Disentangling neural cell diversity using single-cell transcriptomics
Poulin, J.-F., Tasic, B., Hjerling-Leffler, J., Trimarchi, J. M., & Awatramani, R. (2016) · Nature Neuroscience · doi:10.1038/nn.4366 · Cited by 293 · see citing works
Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches
Poulin, J.-F., Gaertner, Z., Moreno-Ramos, O. A., & Awatramani, R. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.01.004 · Cited by 238 · see citing works
Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons
Kim, J.-I., Ganesan, S., Luo, S. X., Wu, Y.-W., Park, E., Huang, E. J., Chen, L., & Ding, J. B. (2015) · Science · doi:10.1126/science.aac4690 · Cited by 217 · see citing works
Self-citationDevelopment, wiring and function of dopamine neuron subtypes
Garritsen, O., van Battum, E. Y., Grossouw, L. M., & Pasterkamp, R. J. (2023) · Nature reviews. Neuroscience · doi:10.1038/s41583-022-00669-3 · Cited by 128 · see citing works
Wu, J., Kung, J., Dong, J., Chang, L., Xie, C., Habib, A., Hawes, S., Yang, N., Chen, V., Liu, Z., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.06.095 · Cited by 87 · see citing works
Self-citationKramer, D. J., Risso, D., Kosillo, P., Ngai, J., & Bateup, H. S. (2018) · eNeuro · doi:10.1523/eneuro.0152-18.2018 · Cited by 70 · see citing works
Inhibitory co-transmission from midbrain dopamine neurons relies on presynaptic GABA uptake
Melani, R., & Tritsch, N. X. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110716 · Cited by 56 · see citing works
Sgobio, C., Wu, J., Zheng, W., Chen, X., Pan, J., Salinas, A. G., Davis, M. I., Lovinger, D. M., & Cai, H. (2017) · Scientific Reports · doi:10.1038/s41598-017-05598-1 · Cited by 47 · see citing works
Self-citation
- Authors
- Liu, G., Yu, J., Ding, J., Xie, C., Sun, L., Rudenko, I., Zheng, W., Sastry, N., Luo, J., Rudow, G., Troncoso, J. C., & Cai, H.
- Affiliations
- National Institutes of Health (US)
- Beijing Normal University (CN)
- Johns Hopkins University (US)
- Corresponding author
- Cai, Huaibin
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2014-05-27
- Volume
- 124
- Issue
- 7
- Pages
- 3032-3046
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4071380
- OpenAlex
- W2070635751
- Cited by
- 166
- References
- 48
- Citations by year
- 2026: 24 · 2025: 13 · 2024: 19 · 2023: 9 · 2022: 16 · 2021: 22 · 2020: 13 · 2019: 13 · 2018: 4 · 2017: 13 · 2016: 8 · 2015: 7 · 2014: 5
- FWCI
- 7.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Johns Hopkins University
- National Institutes of Health
- National Institute on Aging (AG000945-03, K07AG000959, AG000959-07, P50AG005146, Z01AG000945, Z01AG000959, P50AG05146)
- National Institute of Neurological Disorders and Stroke (P50NS038377)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- ALDH1, ALDH1A1, dopaminergic neurons, substantia nigra pars compacta, Parkinson's disease, alpha-synuclein, neurodegeneration, neuronal subpopulations, alpha-synuclein aggregation, neuroprotection, MPP+, glutamate excitotoxicity, camptothecin
- MeSH terms
- Aldehyde Dehydrogenase 1 Family, Aldehyde Dehydrogenase, Animals, Disease Models, Animal, Female, Humans, Male, Mice, Mutant Strains, Mice, Transgenic, Nerve Degeneration, Parkinson Disease, Recombinant Proteins, Substantia Nigra, Mice, Knockout, Mutation, Missense, Mutant Proteins, Retinal Dehydrogenase, Mice, alpha-Synuclein, Protein Multimerization, Dopaminergic Neurons
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
