GDNF/RET Signaling Pathway Activation Eliminates Lewy Body Pathology in Midbrain Dopamine Neurons

ABSTRACT Background Parkinson's disease (PD) is associated with proteostasis disturbances and accumulation of misfolded α‐synuclein (α‐syn), a cytosolic protein present in high concentrations at pre‐synaptic neuronal terminals. It is a primary constituent of intracellular protein aggregates known as Lewy neurites or Lewy bodies. Progression of Lewy pathology caused by the prion‐like self‐templating properties of misfolded α‐syn is a characteristic feature in the brains of PD patients. Glial cell line‐derived neurotrophic factor (GDNF) promotes survival of mature dopamine (DA) neurons in vitro and in vivo. However, the data on its effect on Lewy pathology is controversial. Objectives We studied the effects of GDNF on misfolded α‐syn accumulation in DA neurons. Methods Lewy pathology progression was modeled by the application of α‐syn preformed fibrils in cultured DA neurons and in the adult mice. Results We discovered that GDNF prevented accumulation of misfolded α‐syn in DA neurons in culture and in vivo. These effects were abolished by deletion of receptor tyrosine kinase rearranged during transfection (RET) or by inhibitors of corresponding signaling pathway. Expression of constitutively active RET protected DA neurons from fibril‐induced α‐syn accumulation. Conclusions For the first time, we have shown the neurotrophic factor‐mediated protection against the misfolded α‐syn propagation in DA neurons, uncovered underlying receptors, and investigated the involved signaling pathways. These results demonstrate that activation of GDNF/RET signaling can be an effective therapeutic approach to prevent Lewy pathology spread at early stages of PD. © 2020 International Parkinson and Movement Disorder Society