Investigation of Insulin Signaling in Parkinson's Disease Cytoplasmic Hybrid Cells

Abstract

Neurodegenerative diseases, including Parkinson's disease (PD), have been linked to Type 2 Diabetes (T2D), and impaired mitochondrial function occurs in both diseases. A cell model of PD, the PD cytoplasmic hybrid (cybrid), contains mitochondrial DNA from PD patients. Control (CTL) cybrids contain mitochondrial DNA from healthy individuals. PD cybrids exhibit increased stress kinase activity (JNK and IkKB) compared with CTL cybrids. Because stress kinases are linked to insulin resistance, we hypothesized that PD cybrids would exhibit deficits in insulin signaling. The aim of this study was twofold: to characterize differences in insulin signaling between PD and CTL cybrids and to investigate the impact of increased heat shock protein (HSP) expression on insulin signaling. Insulin resistance occurs due to post‐receptor serine phosphorylation of the insulin receptor substrate (IRS) proteins. Compared to CTL cybrid lines, PD cybrids exhibited increased serine phosphorylation of IRS2, the primary IRS in the brain, and increased JNK activation. In addition, heat treatment resulted in HSP70 upregulation and a concomitant decrease in IRS2 serine phosphorylation in PD cybrids. HSPs can inhibit the action of stress kinases, which is a potential mechanism for decreased IRS2 serine phosphorylation. Upregulation of HSPs may be a valuable intervention in preventing insulin resistance in PD.