GDNF/RET signaling pathway activation eliminates Lewy Body pathology in midbrain dopamine neurons

Abstract

Neurodegenerative diseases are associated with proteostasis disturbances and accumulation of fibrillar proteins into insoluble aggregates. Progressive age-related degeneration of dopamine neurons is a primary cause of motor dysfunctions in Parkinsons disease (PD) and substantial evidence supports critical involvement of -synuclein (-syn) in the etiology of PD. -syn is a cytosolic protein present in high concentrations in pre-synaptic neuronal terminals and a primary constituent of intracellular protein aggregates known as Lewy Neurites or Lewy Bodies. Progression of Lewy pathology is a characteristic feature in the PD brains caused by the prion-like self-templating properties of misfolded -syn. Modelling Lewy pathology progression with application of exogenously prepared -syn preformed fibrils, we discovered that glial cell line-derived neurotrophic factor (GDNF) prevented formation of -syn aggregates in dopamine neurons in culture and in vivo after viral vector expression of GDNF. These effects were abolished by CRISPR/Cas9-mediated deletion of receptor tyrosine kinase Ret, the major GDNF signaling pathway. Similar to GDNF, expression of mutated constitutively active RET (RET_MEN2B) was able to protect dopamine neurons. GDNF protection against -syn pathology progression was abolished by Src and attenuated by Akt pathway inhibitors. For the first time, we have shown the neurotrophic factor-mediated protection against the misfolded -syn propagation in dopamine neurons, uncovered underlying receptor and intracellular signaling pathways. These results for the first time demonstrate that activation of GDNF/RET signaling can be an effective therapeutic approach to prevent Lewy pathology spread at early stages of PD.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=145 HEIGHT=200 SRC=\"FIGDIR/small/752899v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (57K):\norg.highwire.dtl.DTLVardef@1f5109dorg.highwire.dtl.DTLVardef@15e4a2org.highwire.dtl.DTLVardef@15571c8org.highwire.dtl.DTLVardef@a10f7d_HPS_FORMAT_FIGEXP M_FIG C_FIG