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Discoidin Domain Receptor 1 is a therapeutic target for neurodegenerative diseases.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2020 Oct 10; Vol. 29 (17), pp. 2882-2898. - Publication Year :
- 2020
-
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.<br /> (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Alzheimer Disease complications
Alzheimer Disease drug therapy
Alzheimer Disease genetics
Alzheimer Disease pathology
Animals
Discoidin Domain Receptor 1 antagonists & inhibitors
Disease Models, Animal
Humans
Inflammation complications
Inflammation drug therapy
Inflammation genetics
Inflammation pathology
Lewy Body Disease genetics
Lewy Body Disease pathology
Mice
MicroRNAs genetics
Neurodegenerative Diseases pathology
Parkinson Disease complications
Parkinson Disease genetics
Parkinson Disease pathology
Pyrimidines pharmacology
Discoidin Domain Receptor 1 genetics
Lewy Body Disease drug therapy
Neurodegenerative Diseases genetics
Parkinson Disease drug therapy
alpha-Synuclein genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 29
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 32776088
- Full Text :
- https://doi.org/10.1093/hmg/ddaa177