Discoidin Domain Receptor 1 is a therapeutic target for neurodegenerative diseases

Author:

Fowler Alan J123,Hebron Michaeline1,Balaraman Kaluvu4,Shi Wangke1,Missner Alexander A1,Greenzaid Jonathan D1,Chiu Timothy L1,Ullman Clementina1,Weatherdon Ethan1,Duka Val1,Torres-Yaghi Yasar5,Pagan Fernando L5,Liu Xiaoguang1,Ressom Habtom6,Ahn Jaeil7,Wolf Christian4,Moussa Charbel12

Affiliation:

1. Department of Neurology, Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Lewy Body Dementia Association, Research Center of Excellence, Georgetown University Medical Center, Washington, DC 20057, USA

2. Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA

3. Georgetown Howard Universities Center for Clinical and Translational Sciences, Translational Biomedical Sciences Program, Georgetown University Medical Center, Washington, DC 20057, USA

4. Department of Chemistry, Georgetown University and Medicinal Chemistry Shared Resource, Georgetown University Medical Center, Washington, DC 20057, USA

5. MedStar Georgetown University Hospital, Movement Disorders Clinic, Department of Neurology, Washington, DC 20057, USA

6. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA

7. Department of Bioinformatics, Biostatistics, and Biomathematics, Georgetown University Medical Center, Washington, DC 20057, USA

Abstract

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.

Funder

Georgetown University

National Center for Advancing Translational Sciences

National Institutes of Health

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology,General Medicine

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