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

Chmielarz, P.; Er, S.; Konovalova, J.; Bandres, L.; Hlushchuk, I.; Albert, K.; Panhelainen, A.; Luk, K. C.; Airavaara, M.; Domanskyi, A.

doi:10.1101/752899

bioRxiv · 10.1101/752899

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

Chmielarz, P.·Er, S.·Konovalova, J.·Bandres, L.·Hlushchuk, I.·Albert, K.·Panhelainen, A.·Luk, K. C.·Airavaara, M.·Domanskyi, A.

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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

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Chmielarz, P., Er, S., Konovalova, J., Bandres, L., Hlushchuk, I., Albert, K., Panhelainen, A., Luk, K. C., Airavaara, M., Domanskyi, A.. 2019-09-02. GDNF/RET signaling pathway activation eliminates Lewy Body pathology in midbrain dopamine neurons. https://doi.org/10.1101/752899

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