β2-adrenergic Agonists Rescue Lysosome Acidification and Function in PSEN1 Deficiency by Reversing Defective ER-to-lysosome Delivery of ClC-7.,Journal of Molecular Biology

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β2-adrenergic Agonists Rescue Lysosome Acidification and Function in PSEN1 Deficiency by Reversing Defective ER-to-lysosome Delivery of ClC-7.
Journal of Molecular Biology ( IF 4.7 ) Pub Date : 2020-02-24 , DOI: 10.1016/j.jmb.2020.02.021
Ju-Hyun Lee ₁ , Devin M Wolfe ₂ , Sandipkumar Darji ₂ , Mary Kate McBrayer ₂ , Daniel J Colacurcio ₂ , Asok Kumar ₂ , Philip Stavrides ₂ , Panaiyur S Mohan ₁ , Ralph A Nixon ₃

Affiliation

Lysosomal dysfunction is considered pathogenic in Alzheimer disease (AD). Loss of presenilin-1 (PSEN1) function causing AD impedes acidification via defective vacuolar ATPase (vATPase) V0a1 subunit delivery to lysosomes. We report that isoproterenol (ISO) and related β2-adrenergic agonists reacidify lysosomes in PSEN1 Knock out (KO) cells and fibroblasts from PSEN1 familial AD patients, which restores lysosomal proteolysis, calcium homeostasis, and normal autophagy flux. We identify a novel rescue mechanism involving Portein Kinase A (PKA)-mediated facilitation of chloride channel-7 (ClC-7) delivery to lysosomes which reverses markedly lowered chloride (Cl-) content in PSEN1 KO lysosomes. Notably, PSEN1 loss of function impedes Endoplasmic Reticulum (ER)-to-lysosome delivery of ClC-7. Transcriptomics of PSEN1-deficient cells reveals strongly downregulated ER-to-lysosome transport pathways and reversibility by ISO, thus accounting for lysosomal Cl- deficits that compound pH elevation due to deficient vATPase and its rescue by β2-adrenergic agonists. Our findings uncover a broadened PSEN1 role in lysosomal ion homeostasis and novel pH modulation of lysosomes through β2-adrenergic regulation of ClC-7, which can potentially be modulated therapeutically.

中文翻译：

β2-肾上腺素能激动剂通过逆转ClC-7的ER到溶酶体的有缺陷传递来挽救PSEN1缺陷的溶酶体酸化和功能。

溶酶体功能障碍被认为是阿尔茨海默病（AD）的致病性。导致AD的早老素1（PSEN1）功能丧失会通过液泡ATPase（vATPase）V0a1亚基向溶酶体的传递而阻碍酸化。我们报告说，异丙肾上腺素（ISO）和相关的β2-肾上腺素能激动剂使PSEN1家族性AD患者的PSEN1敲除（KO）细胞和成纤维细胞中的溶酶体重新酸化，从而恢复了溶酶体蛋白水解，钙稳态和正常的自噬通量。我们确定了一种新型的救援机制，涉及门蛋白酶激酶A（PKA）介导的向溶酶体传递氯离子通道7（ClC-7）的促进作用，从而逆转了PSEN1 KO溶酶体中明显降低的氯离子（Cl-）含量。值得注意的是，PSEN1功能丧失会阻止内质网（ER）向溶酶体传递ClC-7。PSEN1缺陷细胞的转录组学揭示了ER到溶酶体的运输途径被强烈下调以及ISO的可逆性，因此解释了溶酶体Cl缺陷，该缺陷导致复合物由于缺乏vATPase而导致pH升高，并被β2-肾上腺素能激动剂拯救。我们的发现揭示了PSEN1在溶酶体离子稳态中的广泛作用以及通过ClC-7的β2-肾上腺素能调节溶酶体的新型pH调节，这可能在治疗中得到调节。

更新日期：2020-02-24

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