Impaired brain insulin signalling in Parkinson's disease

Aims Brain insulin resistance (i.e., decreased insulin/insulin‐like growth factor‐1 [IGF‐1] signalling) may play a role in the pathophysiology of Parkinson's disease (PD), and several anti‐diabetic drugs have entred clinical development to evaluate their potential disease‐modifying properties in PD. A measure of insulin resistance is the amount of the downstream messenger insulin receptor substrate‐1 that is phosphorylated at serine residues 312 (IRS‐1pS312) or 616 (IRS‐1pS616). We assessed IRS‐1pS312 and IRS‐1pS616 expression in post‐mortem brain tissue of PD patients and a preclinical rat model based on viral‐mediated expression of A53T mutated human α‐synuclein (AAV2/9‐h‐α‐synA53T). Methods IRS‐1pS312 and IRS‐1pS616 staining intensity were determined by immunofluorescence in both neurons and glial cells in the substantia nigra pars compacta (SNc) and putamen of PD patients and controls without known brain disease. We further explored a possible relation between α‐synuclein aggregates and brain insulin resistance in PD patients. Both insulin resistance markers were also measured in the SNc and striatum of AAV2/9‐h‐α‐synA53T rats. Results We found higher IRS‐1pS312 staining intensity in nigral dopaminergic neurons and a trend for higher IRS‐1pS312 staining intensity in putaminal neurons of PD patients. We observed no differences for IRS‐1pS616 staining intensity in neurons or IRS‐1pS312 staining intensity in glial cells. IRS‐1pS312 showed high co‐localisation within the core of nigral Lewy bodies. Like PD patients, AAV2/9‐h‐α‐synA53T rats showed higher IRS‐1pS312 staining intensity in the SNc and striatum than controls, whereas IRS‐1pS616 was not different between groups. Conclusions Our results provide evidence for brain insulin resistance in PD and support the rationale for repurposing anti‐diabetic drugs for PD treatment. We show altered brain insulin/IGF‐1 signalling in Parkinson's disease (PD) patients as illustrated by increased expression of IRS‐1pS312 in the substantia nigra pars compacta and the putamen. IRS‐1pS312 showed high co‐localisation within nigral Lewy bodies, the neuropathological hallmark feature of PD. We also show that a rat model based on the viral‐mediated expression of mutated human α‐synuclein recapitulates findings in PD patients, suggesting its usefulness for future research assessing the mechanisms of brain insulin resistance and the effects of anti‐diabetics.