Elevated nuclear phosphatase and tensin homolog (PTEN) and altered insulin signaling in substantia nigral region of patients with Parkinson's disease.

Studies showed that 50-80% of Parkinson's disease (PD) patients have been reported with abnormal glucose tolerance. Alterations in glucose and energy metabolism serve as the early molecular event in PD. Although evidences support that the insulin resistance plays a major role in motor and non-motor complications of PD, the underlying mechanism in the pathogenesis of PD is unclear. To address this issue, we investigated the alterations in major components of insulin signaling in nuclear fraction (NF) and whole tissue homogenate (TH) of substantia nigral (SN) region obtained from postmortem PD brain and their age-matched controls. Pathway components include insulin receptor β (IRβ), IR substrate-1 (IRS1), phosphoinositide 3-kinase p85 (PI3K p85), phosphatidylinositol 4,5-bisphosphate (PIP2), phosphatidylinositol (3,4,5)-trisphosphate (PIP3), protein kinase B (PKB/Akt1/2/3) and glycogen synthase kinase-3β (GSK3β). Phosphatase and tensin homolog (PTEN), a negative regulator of insulin signaling cascade was also studied. A significant decrease in nuclear PI3K p85, Akt1/2/3 and PIP3 levels and significant increase in nuclear PTEN and GSK3β levels were observed in SN region of PD brain when compared to the age-matched controls. Consistently, significant decrease in IRβ, IRS1, PI3K p85, Akt1/2/3 and PIP3 levels and increased GSK3β level were observed in TH obtained from SN region of PD brain compared to the control brain. Data from the study suggest that alterations in insulin signaling may play a vital role in the pathogenesis/progression of PD and other related complications. Thus, decreasing nuclear accumulation of PTEN and/or restoring insulin signaling cascade may halt the neurodegeneration in PD.