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  • Discoidin Domain Receptor 1 is a therapeutic target for neurodegenerative diseases.

Discoidin Domain Receptor 1 is a therapeutic target for neurodegenerative diseases.

Human molecular genetics (2020-08-11)
Alan J Fowler, Michaeline Hebron, Kaluvu Balaraman, Wangke Shi, Alexander A Missner, Jonathan D Greenzaid, Timothy L Chiu, Clementina Ullman, Ethan Weatherdon, Val Duka, Yasar Torres-Yaghi, Fernando L Pagan, Xiaoguang Liu, Habtom Ressom, Jaeil Ahn, Christian Wolf, Charbel Moussa, Alan J Fowler, Michaeline Hebron, Kaluvu Balaraman, Wangke Shi, Alexander A Missner, Jonathan D Greenzaid, Timothy L Chiu, Clementina Ullman, Ethan Weatherdon, Val Duka, Yasar Torres-Yaghi, Fernando L Pagan, Xiaoguang Liu, Habtom Ressom, Jaeil Ahn, Christian Wolf, Charbel Moussa
ABSTRACT

The role of Discoidin Domain Receptors (DDRs) is poorly understood in neurodegeneration. DDRs are upregulated in Alzheimer's and Parkinson's disease (PD), and DDRs knockdown reduces neurotoxic protein levels. Here we show that potent and preferential DDR1 inhibitors reduce neurotoxic protein levels in vitro and in vivo. Partial or complete deletion or inhibition of DDR1 in a mouse model challenged with α-synuclein increases autophagy and reduces inflammation and neurotoxic proteins. Significant changes of cerebrospinal fluid microRNAs that control inflammation, neuronal injury, autophagy and vesicular transport genes are observed in PD with and without dementia and Lewy body dementia, but these changes are attenuated or reversed after treatment with the DDR1 inhibitor, nilotinib. Collectively, these data demonstrate that DDR1 regulates autophagy and reduces neurotoxic proteins and inflammation and is a therapeutic target in neurodegeneration.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
G 418 disulfate salt, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Collagen from rat tail, Bornstein and Traub Type I, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Nilotinib
Millipore
MILLIPLEX® Mouse Cytokine/Chemokine Magnetic Bead Panel - Immunology Multiplex Assay, Simultaneously analyze multiple cytokine and chemokine biomarkers with Bead-Based Multiplex Assays using the Luminex technology, in mouse serum, plasma and cell culture samples.