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

View ORCID ProfilePiotr Chmielarz, View ORCID ProfileŞafak Er, Julia Konovalova, Laura Bandrés, Irena Hlushchuk, View ORCID ProfileKatrina Albert, View ORCID ProfileAnne Panhelainen, View ORCID ProfileKelvin Luk, View ORCID ProfileMikko Airavaara, View ORCID ProfileAndrii Domanskyi
doi: https://doi.org/10.1101/752899
Piotr Chmielarz
1Institute of Biotechnology, HiLIFE, University of Helsinki, Finland
2Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Smętna 12, Poland
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Şafak Er
1Institute of Biotechnology, HiLIFE, University of Helsinki, Finland
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Julia Konovalova
1Institute of Biotechnology, HiLIFE, University of Helsinki, Finland
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Laura Bandrés
1Institute of Biotechnology, HiLIFE, University of Helsinki, Finland
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Irena Hlushchuk
1Institute of Biotechnology, HiLIFE, University of Helsinki, Finland
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Katrina Albert
1Institute of Biotechnology, HiLIFE, University of Helsinki, Finland
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Anne Panhelainen
1Institute of Biotechnology, HiLIFE, University of Helsinki, Finland
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Kelvin Luk
3Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Mikko Airavaara
1Institute of Biotechnology, HiLIFE, University of Helsinki, Finland
4Neuroscience Center, HiLIFE, University of Helsinki, Finland
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Andrii Domanskyi
1Institute of Biotechnology, HiLIFE, University of Helsinki, Finland
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  • For correspondence: andrii.domanskyi@helsinki.fi
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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 Parkinson’s disease (PD) and substantial evidence supports critical involvement of α-synuclein (α-syn) in the etiology of PD. α-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 α-syn. Modelling Lewy pathology progression with application of exogenously prepared α-syn preformed fibrils, we discovered that glial cell line-derived neurotrophic factor (GDNF) prevented formation of α-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 α-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 α-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.

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Posted September 02, 2019.
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GDNF/RET signaling pathway activation eliminates Lewy Body pathology in midbrain dopamine neurons
Piotr Chmielarz, Şafak Er, Julia Konovalova, Laura Bandrés, Irena Hlushchuk, Katrina Albert, Anne Panhelainen, Kelvin Luk, Mikko Airavaara, Andrii Domanskyi
bioRxiv 752899; doi: https://doi.org/10.1101/752899
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GDNF/RET signaling pathway activation eliminates Lewy Body pathology in midbrain dopamine neurons
Piotr Chmielarz, Şafak Er, Julia Konovalova, Laura Bandrés, Irena Hlushchuk, Katrina Albert, Anne Panhelainen, Kelvin Luk, Mikko Airavaara, Andrii Domanskyi
bioRxiv 752899; doi: https://doi.org/10.1101/752899

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