| Literature DB >> 32776088 |
Alan J Fowler1,2,3, Michaeline Hebron1, Kaluvu Balaraman4, Wangke Shi1, Alexander A Missner1, Jonathan D Greenzaid1, Timothy L Chiu1, Clementina Ullman1, Ethan Weatherdon1, Val Duka1, Yasar Torres-Yaghi5, Fernando L Pagan5, Xiaoguang Liu1, Habtom Ressom6, Jaeil Ahn7, Christian Wolf4, Charbel Moussa1,2.
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.Entities:
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Year: 2020 PMID： 32776088 PMCID： PMC7566445 DOI： 10.1093/hmg/ddaa177
Source DB: PubMed Journal: Hum Mol Genet ISSN： 0964-6906 Impact factor: 6.150