Different dysregulations of CYFIP1 and CYFIP2 in distinct types of dementia

Abstract

In humans, the cytoplasmic FMR1 interacting protein (CYFIP) family consists of two members, namely CYFIP1 and CYFIP2. Both CYFIP1 and CYFIP2 function in the WAVE regulatory complex (WRC), which regulates actin polymerization. Additionally, these two proteins form a posttranscriptional regulatory complex with the fragile X mental retardation protein (FMRP), which suppresses mRNA translation. Thus, CYFIP1 and CYFIP2 are important signalling regulators at synapses, and mutations in their genes are associated with neurodevelopmental and neuropsychiatric disorders, including intellectual disabilities. Moreover, dysregulation of the CYFIP protein family is involved in Alzheimer's disease (AD). However, the relevance of the CYFIP family in other dementias is largely unknown. Here, we compared CYFIP1/2 protein levels in the post-mortem hippocampus from patients with AD, dementia with Lewy bodies (DLB), vascular dementia (VaD) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Consistent with previous findings, CYFIP2 was reduced in AD hippocampus. In DLB and VaD hippocampus, the protein level of CYFIP2 and CYFIP1 was unaltered. Finally, an increase in the protein level of both CYFIP1 and CYFIP2 was noted in FTLD-TDP hippocampus. These findings reveal that the protein levels of the CYFIP family is distinct in different types of dementia, suggesting that the pathogenesis of these neurodegenerative disorders has divergent impacts on hippocampal synaptic function.