Abstract Neuronal insulin resistance is linked to the pathogenesis of Parkinson’s disease through unclear, but potentially targetable, mechanisms. We delineated neuronal and glial mechanisms of insulin resistance and glucagon-like 1 peptide (GLP-1) receptor agonism in human iPSC models of synucleinopathy, and corroborated our findings in patient samples from a Phase 2 trial of a GLP-1R agonist in Parkinson’s ( NCT01971242 ). Human iPSC models of synucleinopathy exhibit neuronal insulin resistance and dysfunctional insulin signalling, which is associated with inhibition of the neuroprotective Akt pathways, and increased expression of the MAPK-associated p38 and JNK stress pathways. Ultimately, this imbalance is associated with cellular stress, impaired proteostasis, accumulation of α-synuclein, and neuronal loss. The GLP-1R agonist exenatide led to restoration of insulin signalling, associated with restoration of Akt signalling and suppression of the MAPK pathways in neurons. GLP-1R agonism reverses the neuronal toxicity associated with the synucleinopathy, through reduction of oxidative stress, improved mitochondrial and lysosomal function, reduced aggregation of α-synuclein, and enhanced neuronal viability. GLP-1R agonism further suppresses synuclein induced inflammatory states in glia, leading to neuroprotection through non cell autonomous effects. In the exenatide-PD2 clinical trial, exenatide treatment was associated with clinical improvement in individuals with higher baseline MAPK expression (and thus insulin resistance). Exenatide treatment led to a reduction of α-synuclein aggregates, and a reduction in inflammatory cytokine IL-6. Taken together, our patient platform defines the mechanisms of GLP-1R action in neurons and astrocytes, identifies the population likely to benefit from GLP-1R agonism, and highlights the utility of GLP-1R agonism as a disease modifying strategy in synucleinopathies.

GLP1 receptor agonism ameliorates Parkinson’s disease through modulation of neuronal insulin signalling and glial suppression