Cited by 145Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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A molecular pathway of neurodegeneration linking α-synuclein to ApoE and Aβ peptides

Gallardo, Gilbert, Schlüter, Oliver M, Südhof, Thomas C·2008·Nature Neuroscience

DOI 10.1038/nn2058

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Abstract

Pathogenic aggregates of alpha-synuclein are thought to contribute to the development of Parkinson's disease. Inclusion bodies containing alpha-synuclein are present in Parkinson's disease and other neurodegenerative diseases, including Alzheimer's disease. Moreover, alpha-synuclein mutations are found in cases of familial Parkinson's disease, and transgenic overexpression of alpha-synuclein causes neurodegeneration in mice. The molecular mechanisms involved, however, remain incompletely understood. Here we show that, in transgenic mice, alpha-synuclein induced neurodegeneration involves activation of the ubiquitin/proteasome system, a massive increase in apolipoprotein E (ApoE) levels and accumulation of insoluble mouse Abeta. ApoE was not protective, but was injurious, as deletion of ApoE delayed the neurodegeneration caused by alpha-synuclein and suppressed the accumulation of Abeta. Our data reveal a molecular link between central pathogenic mechanisms implicated in Parkinson's disease and Alzheimer's disease and suggest that intracellular alpha-synuclein is pathogenic, at least in part, by activation of extracellular signaling pathways involving ApoE.

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Liehn, E. A., Ponomariov, V., Diaconu, R., Streață, I., Ioana, M. I., Crespo-Avilan, G. E., Hernández‐Reséndiz, S., & Cabrera-Fuentes, H. A. (2018) · Archives of Medical Research · doi:10.1016/j.arcmed.2018.08.008 · Cited by 30
Mitochondrial Pathobiology in Parkinson's Disease and Amyotrophic Lateral Sclerosis
Martin, L. J. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100348 · Cited by 32
Effect of Tiantai No.1 (天泰1号) on β-amyloid-induced neurotoxicity and NF-κ B and cAMP responsive element-binding protein
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OMA1 protease eliminates arrested protein import intermediates upon mitochondrial depolarization
Krakowczyk, M., Lenkiewicz, A. M., Sitarz, T., Malińska, D., Borrero-Landazabal, M. A., Mussulini, B. H. M., Linke, V., Szczepankiewicz, A. A., Biazik, J. M., Wydrych, A., et al. (2024) · The Journal of Cell Biology · doi:10.1083/jcb.202306051 · Cited by 37
“Likewise, the PD-associated variant of α -synuclein was observed to associate with mitochondria, interact with TOM translocase, and inhibit mitochondrial protein import (Gallardo et al., 2008; Di Maio et al., 2016).”
A novel resource for studying function and dysfunction of α-synuclein: mouse lines for modulation of endogenous Snca gene expression
Ninkina, N. N., Connor‐Robson, N., Ustyugov, A. A., Tarasova, T. V., Shelkovnikova, T. A., & Buchman, V. L. (2015) · Scientific Reports · doi:10.1038/srep16615 · Cited by 29
Modulation of α-synuclein expression in transgenic animals for modelling synucleinopathies — is the juice worth the squeeze?
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GFAP reactivity, apolipoprotein E redistribution and cholesterol reduction in human astrocytes treated with α-synuclein
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Is malfunction of the ubiquitin proteasome system the primary cause of α-synucleinopathies and other chronic human neurodegenerative disease?
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Cross interactions between Apolipoprotein E and amyloid proteins in neurodegenerative diseases
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“A molecular link between α-Syn, ApoE and Aβ has also been revealed in a study with transgenic mice expressing either wild type or mutant α-Syn [111].”
Background
Actin Aggregations Mark the Sites of Neurite Initiation
Zhang, S.-X., Duan, L., Qian, H., & Yu, X. (2016) · Neuroscience Bulletin · doi:10.1007/s12264-016-0012-2 · Cited by 27
Behavioral Phenotyping of Mouse Models of Neurodegeneration
Dumont, M. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-328-8_15 · Cited by 25
Hindering of proteinopathy-induced neurodegeneration as a new mechanism of action for neuroprotectors and cognition enhancing compounds
Бачурин, С. О., Ustyugov, A. A., Peters, O. M., Shelkovnikova, T. A., Buchman, V. L., & Ninkina, N. N. (2009) · Doklady Biochemistry and Biophysics · doi:10.1134/s1607672909050032 · Cited by 24
Cerebrospinal fluid apolipoprotein E concentration decreases after seizure
Wang, L., Han, Y., Chen, D., Xiao, Z., Xi, Z., Xiao, F., & Wang, X. (2010) · Seizure · doi:10.1016/j.seizure.2009.12.001 · Cited by 23
RGS5 augments astrocyte activation and facilitates neuroinflammation via TNF signaling
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The MPTP neurotoxic lesion model of Parkinson's disease activates the apolipoprotein E cascade in the mouse brain
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Role of Sporadic Parkinson Disease Associated Mutations A18T and A29S in Enhanced α-Synuclein Fibrillation and Cytotoxicity
Kumar, S., Jangir, D. K., Kumar, R., Kumari, M., Bhavesh, N. S., & Maiti, T. K. (2017) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.6b00430 · Cited by 23
Gating deficits in isolation‐reared rats are correlated with alterations in protein expression in nucleus accumbens
Roncada, P., Bortolato, M., Frau, R., Saba, P., Flore, G., Soggiù, A., Pisanu, S., Amoresano, A., Carpentieri, A., & Devoto, P. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05806.x · Cited by 23
“Accordingly, a-syn also participates in a number of intracellular signaling pathways and binds to a broad array of enzymes (Gallardo et al. 2008).”
Background
α-Synuclein Decreases the Abundance of Proteasome Subunits and Alters Ubiquitin Conjugates in Yeast
Popova, B., Gałka, D., Häffner, N., Wang, D., Schmitt, K., Valerius, O., Knop, M., & Braus, G. H. (2021) · Cells · doi:10.3390/cells10092229 · Cited by 24
“Significant alteration in the expression of proteasome subunits was reported in the spinal cord of the A30P αSyn variant in mice [96].”
Background
Dementia in Parkinson's Disease Correlates withα-Synuclein Pathology but Not with Cortical Astrogliosis
van den Berge, S. A., Kevenaar, J. T., Sluijs, J. A., & Hol, E. M. (2012) · Parkinson s Disease · doi:10.1155/2012/420957 · Cited by 22
Understanding the molecular basis of Parkinson’s disease, identification of biomarkers and routes to therapy
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Elevated Hapln2 Expression Contributes to Protein Aggregation and Neurodegeneration in an Animal Model of Parkinson's Disease
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“Extraction of RIPA-soluble and RIPA-insoluble protein fractions from brain tissues was described previously (Gallardo et al., 2008; Neumann et al., 2009; Walker et al., 2015; Bandopadhyay, 2016).”
Method
Cytosolic Quality Control of Mitochondrial Protein Precursors—The Early Stages of the Organelle Biogenesis
Lenkiewicz, A. M., Krakowczyk, M., & Brągoszewski, P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010007 · Cited by 18
“Similarly, in Parkinson’s disease, mutant forms of α-synuclein, a small but very abundant soluble protein in the nervous system cells, were associated with mitochondrial membranes [211].”
Background
Apolipoprotein E Gene in α-Synucleinopathies: A Narrative Review
Liampas, I., Kyriakoulopoulou, P., Siokas, V., Tsiamaki, E., Stamati, P., Kefalopoulou, Z. M., Chroni, E., & Dardiotis, E. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031795 · Cited by 30
“Later, interactions between intracellular aS and APOE (protein) dependent pathways were suggested to mediate the stimulation of shared neurodegenerative mechanisms in PD and AD [52].”
Background
Alzheimer’s disease shares gene expression aberrations with purinergic dysregulation of HPRT deficiency (Lesch–Nyhan disease)
Kang, T. H., & Friedmann, T. (2015) · Neuroscience Letters · doi:10.1016/j.neulet.2015.01.042 · Cited by 19
The role of α-synuclein in neurodegeneration — An update
Jellinger, K. A. (2012) · Translational Neuroscience · doi:10.2478/s13380-012-0013-1 · Cited by 19
Apolipoprotein E genotype is related to nitric oxide production in platelets
Marcourakis, T., Bahia, V. S., Kawamoto, E. M., Munhoz, C. D., Gorjão, R., Artes, R., Kok, F., Caramelli, P., Nitríni, R., Curi, R., et al. (2008) · Cell Biochemistry and Function · doi:10.1002/cbf.1516 · Cited by 19
An exploration of the potential mechanisms and translational potential of five medicinal plants for applications in Alzheimer's disease.
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The role of APOE alleles in incident Parkinson’s disease. The Norwegian ParkWest Study
Vefring, H. K., Haugarvoll, K., Tysnes, O., Larsen, J. O., Kurz, M. W., & for the Norwegian ParkWest Study group (2010) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.2010.01362.x · Cited by 19
Identification of Altered Blood MicroRNAs and Plasma Proteins in a Rat Model of Parkinson’s Disease
Yadav, S. K., Pandey, A. K., Sarkar, S., Yadav, S., Parmar, D., & Yadav, S. (2022) · Molecular Neurobiology · doi:10.1007/s12035-021-02636-y · Cited by 18
α-synuclein increases the cellular level of phospholipase Cβ1
Guo, Y., Rosati, B., & Scarlata, S. (2012) · Cellular Signalling · doi:10.1016/j.cellsig.2012.01.007 · Cited by 18
Hyperactive glial cells contribute to axonal pathologies in the spinal cord of Npc1 mutant mice
Yan, X., Yang, F., Lukáš, J., Witt, M., Wree, A., Rolfs, A., & Luo, J. (2014) · Glia · doi:10.1002/glia.22659 · Cited by 17
“Enhanced ApoE in Glial Cells of the Npc12/2 Spinal Cord ApoE has been reported as a genetic risk factor to enhance glial activation, resulting in an increased secretion of cytokines in Alzheimer’s disease (AD; Gallardo et al., 2008; Zhu et al., 2012).”
Background
Apolipoprotein E4, amyloid, and cognition in Alzheimer's and Lewy body disease
Jung, J. H., Jeon, S., Baik, K., Lee, Y. H., Chung, S. J., Yoo, H. S., Jeong, S. H., Sohn, Y. H., Lee, P. H., & Ye, B. S. (2021) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2021.06.004 · Cited by 16
Endogenous Human Proteins Interfering with Amyloid Formation
Gharibyan, A. L., Jayaweera, S. W., Lehmann, M., Anan, I., & Olofsson, A. (2022) · Biomolecules · doi:10.3390/biom12030446 · Cited by 17
“While this could be a defensive response directed to reduce α-syn aggregation and protect from PD, the authors showed that the elevation of ApoE levels is accompanied by Aβ aggregation [157].”
BackgroundInfluential
Cognitive, Neuropsychiatric, and Motor Features Associated With Apolipoprotein E ∊4 Allele in a Sample of Bulgarian Patients With Late-Onset Parkinson’s Disease
Pavlova, R., Mehrabian, S., Petrova, M., Skelina, S., Mihova, K. Y., Jordanova, A., Mitev, V., & Traykov, L. D. (2014) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.1177/1533317514525655 · Cited by 16
“Also, APOE was identified as an important molecular link between central mechanisms in PD and AD, by activation of extracellular signaling pathways.(17) However, in clearly defined cases other authors failed to confirm association of dementia with PD and APOE polymorphisms.”
Result
Neuroprotective actions of norepinephrine in neurological diseases
Ghasemi, M., & Mehranfard, N. (2024) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-024-02999-w · Cited by 16

Authors: Gallardo, G., Schlüter, O. M., & Südhof, T. C.
Affiliations: The University of Texas Southwestern Medical Center (US)
European Neuroscience Institute Göttingen (DE)
Howard Hughes Medical Institute (US)
Corresponding author: Gallardo, Gilbert
ORCID: Gallardo, Gilbert
Schlüter, Oliver M
Südhof, Thomas C
Venue: Nature Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2008-02-24
Volume: 11
Issue: 3
Pages: 301-308
ISSN: 1097-6256 (ISSN-L)
1546-1726
DOI: 10.1038/nn2058
OpenAlex: W1564677510
Cited by: 145
References: 48
Citations by year: 2026: 2 · 2025: 7 · 2024: 8 · 2023: 6 · 2022: 8 · 2021: 6 · 2020: 5 · 2019: 10 · 2018: 9 · 2017: 8 · 2016: 5 · 2015: 6 · 2014: 3 · 2013: 9 · 2012: 13
FWCI: 8.50
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Neuroscience (publishedVersion)
PubMed (publishedVersion)
Funders: Howard Hughes Medical Institute
National Institutes of Health
National Institute of Mental Health (R01MH069585)
Topics: Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: alpha-synuclein, apolipoprotein E, amyloid-beta, Parkinson's disease, Alzheimer's disease, neurodegeneration, ubiquitin-proteasome system, transgenic mice, protein aggregation, extracellular signaling
MeSH terms: Alzheimer Disease, Animals, Apolipoproteins E, Brain, Humans, Mice, Transgenic, Nerve Degeneration, Parkinson Disease, Peptides, Signal Transduction, Amyloid beta-Peptides, Cell Death, Mice, Knockout, Neurodegenerative Diseases, Lewy Body Disease, Ubiquitin, Proteasome Endopeptidase Complex, Mice, alpha-Synuclein

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A molecular pathway of neurodegeneration linking α-synuclein to ApoE and Aβ peptides

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