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Two C-terminal sequence variations determine differential neurotoxicity between human and mouse α-synuclein

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Landeck, Natalie, Strathearn, Katherine E., Ysselstein, Daniel, Buck, Kerstin, Dutta, Sayan, Banerjee, Siddhartha, Lv, Zhengjian, Hulleman, John D. +7 more·2020·Molecular Neurodegeneration
DOI 10.1186/s13024-020-00380-wPMC PMC7487555

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Abstract

Background: α-Synuclein (aSyn) aggregation is thought to play a central role in neurodegenerative disorders termed synucleinopathies, including Parkinson’s disease (PD). Mouse aSyn contains a threonine residue at position 53 that mimics the human familial PD substitution A53T, yet in contrast to A53T patients, mice show no evidence of aSyn neuropathology even after aging. Here, we studied the neurotoxicity of human A53T, mouse aSyn, and various human-mouse chimeras in cellular and in vivo models, as well as their biochemical properties relevant to aSyn pathobiology. Methods: Primary midbrain cultures transduced with aSyn-encoding adenoviruses were analyzed immunocytochemically to determine relative dopaminergic neuron viability. Brain sections prepared from rats injected intranigrally with aSyn-encoding adeno-associated viruses were analyzed immunohistochemically to determine nigral dopaminergic neuron viability and striatal dopaminergic terminal density. Recombinant aSyn variants were characterized in terms of fibrillization rates by measuring thioflavin T fluorescence, fibril morphologies via electron microscopy and atomic force microscopy, and protein-lipid interactions by monitoring membrane-induced aSyn aggregation and aSyn-mediated vesicle disruption. Statistical tests consisted of ANOVA followed by Tukey’s multiple comparisons post hoc test and the Kruskal-Wallis test followed by a Dunn’s multiple comparisons test or a two-tailed Mann-Whitney test. Results: Mouse aSyn was less neurotoxic than human aSyn A53T in cell culture and in rat midbrain, and data obtained for the chimeric variants indicated that the human-to-mouse substitutions D121G and N122S were at least partially responsible for this decrease in neurotoxicity. Human aSyn A53T and a chimeric variant with the human residues D and N at positions 121 and 122 (respectively) showed a greater propensity to undergo membrane-induced aggregation and to elicit vesicle disruption. Differences in neurotoxicity among the human, mouse, and chimeric aSyn variants correlated weakly with differences in fibrillization rate or fibril morphology. Conclusions: Mouse aSyn is less neurotoxic than the human A53T variant as a result of inhibitory effects of two C-terminal amino acid substitutions on membrane-induced aSyn aggregation and aSyn-mediated vesicle permeabilization. Our findings highlight the importance of membrane-induced self-assembly in aSyn neurotoxicity and suggest that inhibiting this process by targeting the C-terminal domain could slow neurodegeneration in PD and other synucleinopathy disorders.

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Authors
Landeck, N., Strathearn, K. E., Ysselstein, D., Buck, K., Dutta, S., Banerjee, S., Lv, Z., Hulleman, J. D., Hindupur, J., Lin, L.-K., Padalkar, S., Stanciu, L. A., Lyubchenko, Y. L., Kirik, D., & Rochet, J.-C.
Affiliations
  • Lund University (SE)
  • Purdue University West Lafayette (US)
  • University of Nebraska Medical Center (US)
Corresponding author
  • Kirik, Deniz
  • Rochet, Jean-Christophe
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2020-09-08
Volume
15
Issue
1
Pages
49-49
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-020-00380-w
PMC
PMC7487555
OpenAlex
W3084325168
Cited by
19
References
5
Citations by year
2026: 3 · 2025: 6 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 1
FWCI
0.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DigitalCommons@UNMC (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Lund University Publications (Lund University) (submittedVersion)
  • Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
Funders
  • Branfman Family Foundation (N/A)
  • Michael J. Fox Foundation for Parkinson's Research (N/A)
  • National Institute of Neurological Disorders and Stroke (NS049221, NS058395-04)
  • National Institute of General Medical Sciences (GM096039)
  • FP7 People: Marie-Curie Actions (238316)
  • European Research Council (242932)
  • Swedish Research Council (2012-2586)
  • Purdue Research Foundation (N/A)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
alpha-synuclein, A53T mutation, Parkinson's disease, synucleinopathies, neurotoxicity, C-terminal sequence, dopaminergic neurons, fibrillization, protein-lipid interactions, transgenic mouse model
MeSH terms
Animals, Humans, Neurons, Rats, Sprague-Dawley, Mice, Rats, alpha-Synuclein, Protein Aggregation, Pathological

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