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Hessler S, Zheng F, Hartmann S, Rittger A, Lehnert S, Völkel M, Nissen M, Edelmann E, Saftig P, Schwake M, Huth T, Alzheimer C. β-Secretase BACE1 regulates hippocampal and reconstituted M-currents in a β-subunit-like fashion. J Neurosci. 2015 Feb 25;35(8):3298-311. PubMed.
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German Center for Neurodegenerative Diseases (DZNE)
Although such a function may seem extremely unusual, it fits with a previous study from the same group and with increasing reports about non-proteolytic functions of other proteases, such as a transcription factor function of MMP-12 in antiviral immunity (see Marchant et al., 2014) or the γ-secretase-independent functions of presenilin in calcium homeostasis (see McBrayer and Nixon, 2013). I am sure that the group will follow up on these observations and demonstrate the direct (functional) interaction of BACE1 with KCNQ proteins in brain. Additionally, it would be great to generate a catalytically inactive BACE1 knock-in line to observe which functions require proteolytically active or inactive BACE1. In any case, the good news for drug development is that the non-proteolytic functions should not be affected by BACE inhibitors.
References:
Marchant DJ, Bellac CL, Moraes TJ, Wadsworth SJ, Dufour A, Butler GS, Bilawchuk LM, Hendry RG, Robertson AG, Cheung CT, Ng J, Ang L, Luo Z, Heilbron K, Norris MJ, Duan W, Bucyk T, Karpov A, Devel L, Georgiadis D, Hegele RG, Luo H, Granville DJ, Dive V, McManus BM, Overall CM. A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity. Nat Med. 2014 May;20(5):493-502. Epub 2014 Apr 28 PubMed.
McBrayer M, Nixon RA. Lysosome and calcium dysregulation in Alzheimer's disease: partners in crime. Biochem Soc Trans. 2013 Dec;41(6):1495-502. PubMed.
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