期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 25, 期 9, 页码 4516-4521出版社
WILEY
DOI: 10.1111/jcmm.16474
关键词
CSF1R; CSF1R I794T variant; proteolytic shedding; TREM2
资金
- National Natural Science Foundation of China [91949129, 81771164, 81771377, U1705285, 92049202]
- National Innovative Training Programme for College Students of Xiamen University [2018X0589, S201910384499]
- Open Research Funds of State Key Laboratory of Cellular Stress Biology, Xiamen University [SKLCSB2019KF014]
- National Key Research and Development Program of China [2018YFC2000400, 2016YFC1305903]
- Natural Science Foundation of Fujian Province of China [2018D0022, 2020J01014]
Recent research has found that shedding of CSF1R and TREM2 may play a role in neurodegenerative diseases, particularly the CSF1R I794T variant. Inhibition of shedding was shown to decrease cleaved fragments associated with the I794T variant, suggesting that the cleaved ectodomain fragment may serve as a diagnostic biomarker for ALSP.
Both Colony-stimulating factor 1 receptor (CSF1R) and triggering receptor expressed on myeloid cells-2 (TREM2) are trans-membrane receptors and are expressed in the brain primarily by microglia. Mutations in these two microglia-expressed genes associated with neurodegenerative disease have recently been grouped under the term microgliopathy. Several literatures have indicated that CSF1R and TREM2 encounters a stepwise shedding and TREM2 variants impair or accelerate the processing. However, whether CSF1R variant affects the shedding of CSF1R remains elusive. Here, plasmids containing human CSF1R or TREM2 were transiently transfected into the human embryonic kidney (HEK) 293T cells. Using Western Blot and/or ELISA assay, we demonstrated that, similar to those of TREM2, an N-terminal fragment (NTF) shedding of CSF1R ectodomain and a subsequent C-terminal fragment (CTF) of CSF1R intra-membrane were generated by a disintegrin and metalloprotease (ADAM) family member and by gamma-secretase, respectively. And the shedding was inhibited by treatment with Batimastat, an ADAM inhibitor, or DAPT or compound E, a gamma-secretase inhibitor. Importantly, we show that the cleaved fragments, both extracellular domain and intracellular domain of a common disease associated I794T variant, were decreased significantly. Together, our studies demonstrate a stepwise approach of human CSF1R cleavage and contribute to understand the pathogenicity of CSF1R I794T variant in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). These studies also suggest that the cleaved ectodomain fragment released from CSF1R may be proposed as a diagnostic biomarker for ALSP.
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