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Systematic Mutagenesis of α-Synuclein Reveals Distinct Sequence Requirements for Physiological and Pathological Activities
Open accessAbstract
α-Synuclein is an abundant presynaptic protein that binds to phospholipids and synaptic vesicles. Physiologically, α-synuclein functions as a SNARE-protein chaperone that promotes SNARE-complex assembly for neurotransmitter release. Pathologically, α-synuclein mutations and α-synuclein overexpression cause Parkinson's disease, and aggregates of α-synuclein are found as Lewy bodies in multiple neurodegenerative disorders (“synucleinopathies”). The relation of the physiological functions to the pathological effects of α-synuclein remains unclear. As an initial avenue of addressing this question, we here systematically examined the effect of α-synuclein mutations on its physiological and pathological activities. We generated 26 α-synuclein mutants spanning the entire molecule, and analyzed them compared with wild-type α-synuclein in seven assays that range from biochemical studies with purified α-synuclein, to analyses of α-synuclein expression in cultured neurons, to examinations of the effects of virally expressed α-synuclein introduced into the mouse substantia nigra by stereotactic injections. We found that both the N-terminal and C-terminal sequences of α-synuclein were required for its physiological function as SNARE-complex chaperone, but that these sequences were not essential for its neuropathological effects. In contrast, point mutations in the central region of α-synuclein, referred to as nonamyloid β component (residues 61–95), as well as point mutations linked to Parkinson's disease (A30P, E46K, and A53T) increased the neurotoxicity of α-synuclein but did not affect its physiological function in SNARE-complex assembly. Thus, our data show that the physiological function of α-synuclein, although protective of neurodegeneration in some contexts, is fundamentally distinct from its neuropathological effects, thereby dissociating the two activities of α-synuclein.
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Cites
Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis
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BackgroundAlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease
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Mice Lacking α-Synuclein Display Functional Deficits in the Nigrostriatal Dopamine System
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Self-citationMasliah, E., Rockenstein, E., Veinbergs, I., Sagara, Y., Mallory, M., Hashimoto, M., & Mucke, L. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.211412398 · Cited by 607
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Cited by
Goedert, M., Spillantini, M. G., Del Tredici, K., & Braak, H. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.242 · Cited by 1,190
α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies
Wong, Y. C., & Krainc, D. (2017) · Nature Medicine · doi:10.1038/nm.4269 · Cited by 897
Cell Biology and Pathophysiology of α-Synuclein
Burré, J., Sharma, M., & Südhof, T. C. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024091 · Cited by 579
Self-citationThe Synaptic Function of α-Synuclein
Burré, J. (2015) · Journal of Parkinson's Disease · doi:10.3233/jpd-150642 · Cited by 573
Self-citationPhysicochemical Properties of Cells and Their Effects on Intrinsically Disordered Proteins (IDPs)
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Metadata
- Authors
- Burré, J., Sharma, M., & Südhof, T. C.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-10-24
- Volume
- 32
- Issue
- 43
- Pages
- 15227-15242
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- OpenAlex
- W2044141286
- Cited by
- 178
- References
- 10
- FWCI
- 8.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Burré, J., Sharma, M., & Südhof, T. C. (2012). Systematic Mutagenesis of α-Synuclein Reveals Distinct Sequence Requirements for Physiological and Pathological Activities. The Journal of Neuroscience. https://doi.org/10.1523/jneurosci.3545-12.2012
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