Abstract
Characterizing the normal function(s) of the protein α-Synuclein (aSyn) has the potential to illuminate links between Parkinson’s disease (PD) and diabetes and also point the way toward new therapies for these disorders. Here we provide a perspective for consideration based on our discovery that aSyn normally acts to inhibit insulin secretion from pancreatic β-cells by interacting with the Kir6.2 subunit of the ATP-sensitive potassium channel (K-ATP). It is also known that K-ATP channels act to inhibit brain dopamine secretion, and we have also shown that aSyn is a normal inhibitor of dopamine synthesis. The finding, that aSyn modulates Kir6.2 and other proteins involved in dopamine and insulin secretion, suggests that aSyn interacting proteins may be negatively impacted when aSyn aggregates inside cells, whether in brain or pancreas. Furthermore, identifying therapies for PD that can counteract dysfunction found in diabetes, would be highly beneficial. One such compound may be the multiple sclerosis drug, FTY720, which like aSyn can stimulate the activity of the catalytic subunit of protein phosphatase 2A (PP2Ac) as well as insulin secretion. In aging aSyn transgenic mice given long term oral FTY720, the mice had reduced aSyn pathology and increased levels of the protective molecule, brain derived neurotrophic factor (BDNF) (Vidal-Martinez et al., 2016). In collaboration with medicinal chemists, we made two non-immunosuppressive FTY720s that also enhance PP2Ac activity, and BDNF expression (Vargas-Medrano et al., 2014; Enoru et al., 2016; Segura-Ulate et al., 2017a). FTY720 and our novel FTY720-based-derivatives, may thus have therapeutic potential for both diabetes and PD.
Highlights
We provide a perspective for consideration based on our discovery that aSyn normally acts to inhibit insulin secretion from pancreatic β-cells by interacting with the Kir6.2 subunit of the ATPsensitive potassium channel (K-ATP)
It is known that K-ATP channels act to inhibit brain dopamine secretion, and we have shown that aSyn is a normal inhibitor of dopamine synthesis
Alpha-Synuclein, Diabetes, and Parkinson’s Disease has identified several aSyn-interacting proteins and organelles. These include: tyrosine hydroxylase, called tyrosine 3-monooxygenase (EC 1.14.16.2) (TH), the rate limiting dopamine biosynthetic enzyme that localizes on vesicles and mitochondria with aSyn (Perez et al, 2002; Jin et al, 2007; Alerte et al, 2008); the enzyme in the dopamine biosynthetic pathway, aromatic amino acid decarboxylase, AADC, called dopa decarboxylase (Tehranian et al, 2006); the catalytic subunit of protein phosphatase 2A (PP2Ac) (Peng et al, 2005; Lou et al, 2010); and the 14-33ζ adapter protein, which localize to mitochondria to help regulate dopamine synthesis at that organelle (Wang et al, 2009)
Summary
We provide a perspective for consideration based on our discovery that aSyn normally acts to inhibit insulin secretion from pancreatic β-cells by interacting with the Kir6.2 subunit of the ATPsensitive potassium channel (K-ATP). The finding, that aSyn modulates Kir6.2 and other proteins involved in dopamine and insulin secretion, suggests that aSyn interacting proteins may be negatively impacted when aSyn aggregates inside cells, whether in brain or pancreas.
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