. Identification of Alzheimer's disease-associated rare coding variants in the ECE2 gene. JCI Insight. 2020 Feb 27;5(4) PubMed.


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  1. This study by Liao et al. describes a rare AD-associated mutation in the ECE2 gene coding for endothelin-converting enzyme-2, a physiologically relevant Aβ-degrading enzyme. In a Chinese family with a high incidence of AD (father and three of six siblings affected) and no known AD-causing mutations, the missense ECE2 mutation segregated with AD in the siblings. Compared to wild type ECE-2, the mutant enzyme, R186C, had a significant loss of proteolytic activity in an in vitro assay and failed to lower Aβ levels when transfected into HEK293-APPsw cells, or when transduced via AAV into brains of APP knock-in mice.

    The authors went on to screen whole ECE2 gene exomes in 741 AD cases and 545 controls and found that non-synonymous ECE2 variants were significantly overrepresented in AD cases (4.85 percent vs. 0.92 percent, P = 1.6 × 10-4). The result remained significant when restricted to variants predicted to be damaging to the protein. One of these, F751S, confirmed to impair ECE-2 activity, was present in two AD cases but also in one control, highlighting the importance of further evaluating the association of damaging ECE2 variants with AD in larger populations.

    Altogether, the data presented in this paper suggest that partial loss of ECE-2 activity may increase risk for AD by reducing the degradation of Aβ and possibly other substrates. This is consistent with our predictions based on analysis of Ece2 knockout mice, which have a gene dosage-dependent increase in endogenous brain Aβ levels (Eckman et al., 2003) and impaired learning and memory (Rodriguiz et al., 2007). ECE-2 has an acidic pH optimum and is localized exclusively to membranes of intracellular vesicles, including late endosomes, autophagosomes, and multivesicular bodies; its activity is also present in exosomes (Pacheco-Quinto et al., 2019; Pacheco-Quinto et al., 2013). In humans (Allen Cell Types Database) and in mice (Pacheco-Quinto et al., 2016), Ece2 expression is highly enriched in GABAergic interneurons, raising the intriguing possibility that loss of ECE-2 activity may disproportionately affect Aβ accumulation in certain subpopulations of neurons.


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