Insulin Resistance Promotes Parkinson’s Disease through Aberrant Expression of α-Synuclein, Mitochondrial Dysfunction, and Deregulation of the Polo-Like Kinase 2 Signaling

Abstract

Background: Insulin resistance (IR), considered a hallmark of diabetes at the cellular level, is implicated in pre-diabetes, results in type 2 diabetes, and negatively affects mitochondrial function. Diabetes is increasingly associated with enhanced risk of developing Parkinson’s disease (PD); however, the underlying mechanism remains unclear. This study investigated the probable culpability of IR in the pathogenesis of PD. Methods: Using MitoPark mice in vivo models, diabetes was induced by a high-fat diet in the in vivo models, and IR was induced by protracted pulse-stimulation with 100 nM insulin treatment of neuronal cells, in vitro to determine the molecular mechanism(s) underlying altered cellular functions in PD, including mitochondrial dysfunction and α-synuclein (SNCA) aberrant expression. Findings: We observed increased SNCA expression in the dopaminergic (DA) neurons of both the wild-type and diabetic MitoPark mice, coupled with enhanced degeneration of DA neurons in the diabetic MitoPark mice. Ex vivo, in differentiated human DA neurons, IR was associated with increased SNCA and reactive oxygen species (ROS) levels, as well as mitochondrial depolarization. Moreover, we demonstrated concomitant hyperactivation of polo-like kinase-2 (PLK2), and upregulated p-SNCA (Ser129) and proteinase K-resistant SNCA proteins level in IR SH-SY5Y cells, however the inhibition of PLK2 reversed IR-related increases in phosphorylated and total SNCA. Similarly, the overexpression of peroxisome proliferator-activated receptor-γ coactivator 1-alpha (PGC)-1α suppressed ROS production, repressed PLK2 hyperactivity, and resulted in downregulation of total and Ser129-phosphorylated SNCA in the IR SH-SY5Y cells. Conclusions: These findings demonstrate that IR-associated diabetes promotes the development and progression of PD through PLK2-mediated mitochondrial dysfunction, upregulated ROS production, and enhanced SNCA signaling, suggesting the therapeutic targetability of PLK2 and/or SNCA as potential novel disease-modifying strategies in patients with PD.

Transcriptional Profiling and Biological Pathway(s) Analysis of Type 2 Diabetes Mellitus in a Pakistani Population

“…Insulin resistance is the hallmark of diabetes at the cellular level and negatively affects mitochondrial function [88]. Our IPA analysis suggests that several relevant canonical pathways are affected by T2DM, i.e., Mitochondrial Dysfunctions and Insulin Receptor Signaling (Figure 2).…”

Diabetes Mellitus and Parkinson's Disease: Shared Pathophysiological Links and Possible Therapeutic Implications

“…IR also led to increased prolonged oxidative stress and raised aberrant section of α-synuclein. They noticed increased expression of α-synuclein in the diabetic MitoPark mice and enhanced degeneration of the dopaminergic neurons [19]. Moreover, IR leads to increased α-synuclein, oxidative stress, and mitochondrial dysfunction in differentiated human dopaminergic cells [5,19].…”

“…They noticed increased expression of α-synuclein in the diabetic MitoPark mice and enhanced degeneration of the dopaminergic neurons [19]. Moreover, IR leads to increased α-synuclein, oxidative stress, and mitochondrial dysfunction in differentiated human dopaminergic cells [5,19]. A study carried out in insulin-resistant mice revealed a loss of dopaminergic neurons and abnormal movement similar to PD.…”

Altered Insulin Receptor Substrate 1 Phosphorylation in Blood Neuron-Derived Extracellular Vesicles From Patients With Parkinson’s Disease

“…In addition, diabetes and poor blood sugar control are linked to fast deterioration and worse PD severity ( Cereda et al, 2012 ; Kotagal et al, 2013 ). Although insulin resistance or diabetes enhances PD-related pathogeneses in in vivo and in vitro neuronal models ( Bousquet et al, 2012 ; Solmaz et al, 2017 ; Hong et al, 2020 ), biological evidence in human studies is lacking and the functional assessment of insulin signaling pathway in PD patients’ neurons is challenging. The fasting or postprandial blood glucose and HbA1c test reflect the pancreatic islet function but not insulin resistance ( Desimone and Weinstock, 2000 ).…”

“…Alzheimer disease (AD), the most common neurodegenerative disease, is speculated to be associated with neural insulin resistance because the major AD pathogeneses, such as neurofibrillary tangles, neuroinflammation, oxidative stress, and neurodegeneration, are all associated with neural insulin resistance ( Arnold et al, 2018 ). Furthermore, several studies have suggested that diabetes increases the risk of or accelerates the progression of Parkinson’s disease (PD), ( Hu et al, 2007 ; Cereda et al, 2011 ; Sun et al, 2012 ; Lu et al, 2014 ; Hong et al, 2020 ). Moreover, no biomarker evidence exists to confirm the association between PD and neural insulin resistance.…”