The function of synuclein

• Autorzy: Bendor J. , Logan T. , Edwards R.
• Języki publikacji: EN

Abstrakty

EN

The presynaptic protein α‑synuclein has a central role in multiple neurodegenerative disorders including Parkinson’s disease (PD). Like many other proteins that accumulate in these disorders, however, the function of synuclein remains poorly understood. The presynaptic location of synuclein suggests a role in neurotransmitter release and over-expression inhibits synaptic vesicle exocytosis. However, knockout mice have shown little difference from wild type. Recent work has suggested that synuclein may act to bend membranes. However, we have observed no clear effect on endocytosis in triple knockout mice lacking all three synuclein isoforms. We have therefore focused on the process of exocytosis. By imaging the individual exocytic events of large dense core vesicles (LDCVs) in adrenal chromaffin cells and in neurons, we have found that both endogenous and over-expressed human synuclein promote dilation of the exocytic fusion pore. As with synaptic vesicles, over-expression inhibits LDCV fusion, but the synuclein does not increase the extent of exocytosis. Synuclein thus has two roles in exocytosis: inhibition (by over-expressed protein) and pore dilation (by the endogenous and over-expressed protein). To assess the significance of these findings for degeneration, we examined the effect of mutations associated with PD. Examining two of the best established mutations, we find that both inhibit LDCV exocytosis when over‑expressed, just like wild type human α‑synuclein. However, the mutations completely blocked the role of synuclein in pore dilation. Mutations that cause PD thus appear to act through a selective loss of normal function, without impairing the ability of synuclein to inhibit exocytosis or presumably to aggregate. FINANCIAL SUPPORT: The Giannini Foundation, NIH, Weill Institute for Neuroscience.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2017
• Tom: 77
• Numer: Suppl.1
• Opis fizyczny: p.19

Twórcy

autor

Bendor J.

• Departments of Neurology and Physiology, UCSF School of Medicine, San Francisco, USA

autor

Logan T.

• Departments of Neurology and Physiology, UCSF School of Medicine, San Francisco, USA

autor

Edwards R.

• Departments of Neurology and Physiology, UCSF School of Medicine, San Francisco, USA
• Kavli Institute for Fundamental Neuroscience, San Francisco, USA
• Weill Institute for Neuroscience, San Francisco, USA