Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Thayanidhi, N; Helm, JR; Nycz, DC; Bentley, M; Liang, Y; Hay, JC.
Alpha-synuclein delays endoplasmic reticulum (ER)-to-Golgi transport in mammalian cells by antagonizing ER/Golgi SNAREs.
Mol Biol Cell. 2010; 21(11):1850-1863
Doi: 10.1091/mbc.E09-09-0801
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- Führende Autor*innen der Med Uni Graz
- Hay Jesse
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- Abstract:
- Toxicity of human alpha-synuclein when expressed in simple organisms can be suppressed by overexpression of endoplasmic reticulum (ER)-to-Golgi transport machinery, suggesting that inhibition of constitutive secretion represents a fundamental cause of the toxicity. Whether similar inhibition in mammals represents a cause of familial Parkinson's disease has not been established. We tested elements of this hypothesis by expressing human alpha-synuclein in mammalian kidney and neuroendocrine cells and assessing ER-to-Golgi transport. Overexpression of wild type or the familial disease-associated A53T mutant alpha-synuclein delayed transport by up to 50%; however, A53T inhibited more potently. The secretory delay occurred at low expression levels and was not accompanied by insoluble alpha-synuclein aggregates or mistargeting of transport machinery, suggesting a direct action of soluble alpha-synuclein on trafficking proteins. Co-overexpression of ER/Golgi arginine soluble N-ethylmaleimide-sensitive factor attachment protein receptors (R-SNAREs) specifically rescued transport, indicating that alpha-synuclein antagonizes SNARE function. Ykt6 reversed alpha-synuclein inhibition much more effectively than sec22b, suggesting a possible neuroprotective role for the enigmatic high expression of ykt6 in neurons. In in vitro reconstitutions, purified alpha-synuclein A53T protein specifically inhibited COPII vesicle docking and fusion at a pre-Golgi step. Finally, soluble alpha-synuclein A53T directly bound ER/Golgi SNAREs and inhibited SNARE complex assembly, providing a potential mechanism for toxic effects in the early secretory pathway.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- COP-Coated Vesicles - metabolism
- Cell Line -
- Endoplasmic Reticulum - metabolism
- Endoplasmic Reticulum - ultrastructure
- Golgi Apparatus - metabolism
- Golgi Apparatus - ultrastructure
- Humans -
- Membrane Fusion -
- Protein Transport - physiology
- R-SNARE Proteins - antagonists & inhibitors
- R-SNARE Proteins - chemistry
- R-SNARE Proteins - genetics
- R-SNARE Proteins - metabolism
- Rats -
- Recombinant Fusion Proteins - genetics
- Recombinant Fusion Proteins - metabolism
- alpha-Synuclein - genetics
- alpha-Synuclein - metabolism