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Cited by 11Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

Carboxyl truncation of α-synuclein occurs early and is influenced by human APOE genotype in transgenic mouse models of α-synuclein pathogenesis

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Lloyd, Grace M., Long, Brooke, Quintin, Stephan, Sorrentino, Zachary A., Gorion, Kimberly-Marie M., Bell, Brach M., Carrillo, Denise, Sullivan, Patrick +2 more·2023·Acta Neuropathologica Communications
DOI 10.1186/s40478-023-01623-9PMC PMC10363304
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Abstract

Post-translational modifications to the carboxyl (C) terminus domain of α-synuclein can play an important role in promoting the pathologic aggregation of α-synuclein. Various cleavages that diminish this highly charged, proline-rich region can result in exposure of hydrophobic, aggregation-prone regions, thereby accelerating the aggregation kinetics of α-synuclein into misfolded, pathologic forms. C-terminally truncated forms of α-synuclein are abundant in human diseased brains compared to controls, suggesting a role in disease pathogenesis. Factors that alter the homeostatic proteolytic processing of α-synuclein may ultimately tip the balance towards a progressive disease state. Apolipoprotein E (APOE) has been implicated in the acceleration of cognitive impairment in patients with Lewy body diseases. The APOE4 isoform has been found to cause dysregulation in the endosomal–lysosomal pathway, which could result in altered α-synuclein degradation as a potential mechanism for promoting its pathologic misfolding. Herein, we investigate the spatiotemporal accumulation of C-terminally truncated α-synuclein in a seeded and progressive mouse model of synucleinopathy. Furthermore, we study how this process is influenced in the context of mice that are altered to express either the human APOE3 or APOE4 isoforms. We found that specific C-terminal truncation of α-synuclein occurs at early stages of pathogenesis. We also found that proteolytic processing of this domain differs across various brain regions and is influenced by the presence of different human APOE isoforms. Our data demonstrate an early pathogenic role for C-terminally truncated α-synuclein, and highlight the influence of APOE isoforms in modulating its impact.

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  • Further mouse studies have shown that APOE4 alters the proteolytic processing of α-synuclein.

    “and further mouse studies have shown that APOE4 alters the proteolytic processing of αSyn.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [133]

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Authors
Lloyd, G. M., Long, B., Quintin, S., Sorrentino, Z. A., Gorion, K.-M. M., Bell, B. M., Carrillo, D., Sullivan, P., Borchelt, D., & Giasson, B. I.
Affiliations
  • University of Florida Health (US)
  • University of Florida (US)
  • Duke University (US)
Corresponding author
Giasson, Benoit I.
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2023-07-23
Volume
11
Issue
1
Pages
119-119
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-023-01623-9
PMC
PMC10363304
OpenAlex
W4385159150
Cited by
11
References
4
Citations by year
2026: 2 · 2025: 3 · 2024: 5 · 2023: 1
FWCI
1.86
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of Neurological Disorders and Stroke (R01NS089022, R01NS100876, RF1NS129567, T32NS082168)
  • National Institute on Aging (RF1AG057933, F30AG063446)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
alpha-synuclein, C-terminal truncation, post-translational modification, apolipoprotein E, APOE ε4, APOE3, synucleinopathies, Lewy body disease, protein aggregation, proteolytic processing, endolysosomal pathway, transgenic mouse model, regional brain differences
MeSH terms
Animals, Apolipoproteins E, Carrier Proteins, Humans, Mice, Transgenic, Protein Isoforms, Mice, alpha-Synuclein, Apolipoprotein E4

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