Splice isoform and pharmacological studies reveal that sterol depletion relocalizes -synuclein and enhances its toxicity
Synucleinopathies are neurodegenerative diseases associated with toxicity of the lipid-binding protein α-synuclein (α-syn). When expressed in yeast, α-syn associates with membranes at the endoplasmic reticulum and traffics with vesicles out to the plasma membrane. At higher levels it elicits a numbe...
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2014
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| Online Access: | http://hdl.handle.net/1721.1/90354 https://orcid.org/0000-0003-1307-882X |
| _version_ | 1826194564843569152 |
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| author | Termine, Daniel J. Lindquist, Susan Valastyan, Julie Suzanne |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Termine, Daniel J. Lindquist, Susan Valastyan, Julie Suzanne |
| author_sort | Termine, Daniel J. |
| collection | MIT |
| description | Synucleinopathies are neurodegenerative diseases associated with toxicity of the lipid-binding protein α-synuclein (α-syn). When expressed in yeast, α-syn associates with membranes at the endoplasmic reticulum and traffics with vesicles out to the plasma membrane. At higher levels it elicits a number of phenotypes, including blocking vesicle trafficking. The expression of α-syn splice isoforms varies with disease, but how these isoforms affect protein function is unknown. We investigated two of the most abundant isoforms, resulting in deletion of exon four (α-synΔ4) or exon six (α-synΔ6). α-SynΔ4, missing part of the lipid-binding domain, had reduced toxicity and membrane binding. α-SynΔ6, missing part of the protein–protein interaction domain, had reduced toxicity but no reduction in membrane binding. To compare the mechanism by which the splice isoforms exert toxicity, equally toxic strains were probed with genetic modifiers of α-syn–induced toxicity. Most modifiers equally altered the toxicity induced by the splice isoforms and full-length α-syn (α-synFL). However, the splice isoform strains responded differently to a sterol-binding protein, leading us to examine the effect of sterols on α-syn–induced toxicity. Upon inhibition of sterol synthesis, α-synFL and α-synΔ6, but not α-synΔ4, showed decreased plasma membrane association, increased vesicular association, and increased cellular toxicity. Thus, higher membrane sterol concentrations favor plasma membrane binding of α-synFL and α-synΔ6 and may be protective of synucleinopathy progression. Given the common use of cholesterol-reducing statins and these potential effects on membrane binding proteins, further investigation of how sterol concentration and α-syn splice isoforms affect vesicular trafficking in synucleinopathies is warranted. |
| first_indexed | 2024-09-23T09:58:13Z |
| format | Article |
| id | mit-1721.1/90354 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:58:13Z |
| publishDate | 2014 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/903542022-09-26T14:53:09Z Splice isoform and pharmacological studies reveal that sterol depletion relocalizes -synuclein and enhances its toxicity Termine, Daniel J. Lindquist, Susan Valastyan, Julie Suzanne Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Valastyan, Julie S. Termine, Daniel J. Lindquist, Susan Synucleinopathies are neurodegenerative diseases associated with toxicity of the lipid-binding protein α-synuclein (α-syn). When expressed in yeast, α-syn associates with membranes at the endoplasmic reticulum and traffics with vesicles out to the plasma membrane. At higher levels it elicits a number of phenotypes, including blocking vesicle trafficking. The expression of α-syn splice isoforms varies with disease, but how these isoforms affect protein function is unknown. We investigated two of the most abundant isoforms, resulting in deletion of exon four (α-synΔ4) or exon six (α-synΔ6). α-SynΔ4, missing part of the lipid-binding domain, had reduced toxicity and membrane binding. α-SynΔ6, missing part of the protein–protein interaction domain, had reduced toxicity but no reduction in membrane binding. To compare the mechanism by which the splice isoforms exert toxicity, equally toxic strains were probed with genetic modifiers of α-syn–induced toxicity. Most modifiers equally altered the toxicity induced by the splice isoforms and full-length α-syn (α-synFL). However, the splice isoform strains responded differently to a sterol-binding protein, leading us to examine the effect of sterols on α-syn–induced toxicity. Upon inhibition of sterol synthesis, α-synFL and α-synΔ6, but not α-synΔ4, showed decreased plasma membrane association, increased vesicular association, and increased cellular toxicity. Thus, higher membrane sterol concentrations favor plasma membrane binding of α-synFL and α-synΔ6 and may be protective of synucleinopathy progression. Given the common use of cholesterol-reducing statins and these potential effects on membrane binding proteins, further investigation of how sterol concentration and α-syn splice isoforms affect vesicular trafficking in synucleinopathies is warranted. Howard Hughes Medical Institute JPB Foundation Howard Hughes Medical Institute (Investigator) National Institutes of Health (U.S.) (National Research and Service Award) 2014-09-25T18:36:28Z 2014-09-25T18:36:28Z 2014-02 2013-12 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/90354 Valastyan, J. S., D. J. Termine, and S. Lindquist. “Splice Isoform and Pharmacological Studies Reveal That Sterol Depletion Relocalizes -Synuclein and Enhances Its Toxicity.” Proceedings of the National Academy of Sciences 111, no. 8 (February 10, 2014): 3014–3019. https://orcid.org/0000-0003-1307-882X en_US http://dx.doi.org/10.1073/pnas.1324209111 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) National Academy of Sciences (U.S.) |
| spellingShingle | Termine, Daniel J. Lindquist, Susan Valastyan, Julie Suzanne Splice isoform and pharmacological studies reveal that sterol depletion relocalizes -synuclein and enhances its toxicity |
| title | Splice isoform and pharmacological studies reveal that sterol depletion relocalizes -synuclein and enhances its toxicity |
| title_full | Splice isoform and pharmacological studies reveal that sterol depletion relocalizes -synuclein and enhances its toxicity |
| title_fullStr | Splice isoform and pharmacological studies reveal that sterol depletion relocalizes -synuclein and enhances its toxicity |
| title_full_unstemmed | Splice isoform and pharmacological studies reveal that sterol depletion relocalizes -synuclein and enhances its toxicity |
| title_short | Splice isoform and pharmacological studies reveal that sterol depletion relocalizes -synuclein and enhances its toxicity |
| title_sort | splice isoform and pharmacological studies reveal that sterol depletion relocalizes synuclein and enhances its toxicity |
| url | http://hdl.handle.net/1721.1/90354 https://orcid.org/0000-0003-1307-882X |
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