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

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Chmielarz , P , Er , S , Konovalova , J , Bandres , L , Hlushchuk , I , Albert , K , Panhelainen , A , Luk , K , Airavaara , M & Domanskyi , A 2020 , ' GDNF/RET Signaling Pathway Activation Eliminates Lewy Body Pathology in Midbrain Dopamine Neurons ' , Movement Disorders , vol. 35 , no. 12 , 2289 , pp. 2279-2289 . https://doi.org/10.1002/mds.28258

Title: GDNF/RET Signaling Pathway Activation Eliminates Lewy Body Pathology in Midbrain Dopamine Neurons
Author: Chmielarz, Piotr; Er, Safak; Konovalova, Julia; Bandres, Laura; Hlushchuk, Irena; Albert, Katrina; Panhelainen, Anne; Luk, Kelvin; Airavaara, Mikko; Domanskyi, Andrii
Contributor: University of Helsinki, Institute of Biotechnology
University of Helsinki, Neuroscience Center
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Regenerative Neuroscience
University of Helsinki, Helsinki One Health (HOH)
University of Helsinki, Neuroscience Center
University of Helsinki, Biosciences
Date: 2020-12-18
Language: eng
Number of pages: 11
Belongs to series: Movement Disorders
ISSN: 0885-3185
URI: http://hdl.handle.net/10138/324699
Abstract: Background Parkinson's disease (PD) is associated with proteostasis disturbances and accumulation of misfolded alpha-synuclein (alpha-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 alpha-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 alpha-syn accumulation in DA neurons. Methods Lewy pathology progression was modeled by the application of alpha-syn preformed fibrils in cultured DA neurons and in the adult mice. Results We discovered that GDNF prevented accumulation of misfolded alpha-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 alpha-syn accumulation. Conclusions For the first time, we have shown the neurotrophic factor-mediated protection against the misfolded alpha-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. (c) 2020 International Parkinson and Movement Disorder Society
Subject: GDNF
Parkinson's disease
alpha-synuclein
dopamine neuron
misfolded protein accumulation
ALPHA-SYNUCLEIN FIBRILS
PARKINSONS-DISEASE
C-ABL
TYROSINE KINASE
LIPID RAFTS
RET
RECEPTOR
NEURODEGENERATION
SRC
3112 Neurosciences
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