Kansl1 haploinsufficiency impairs autophagosome-lysosome fusion and links autophagic dysfunction with Koolen-de Vries syndrome in mice

Dingyi Lu,Ailing Li,Tingting Li,Hua Dong,Xinhua He,Hao Zhang,Guangqin Liu,Qin Han ,Hongbo Zhao ,Hai-Zhen Zhu ,Weina Zhang,Xiaoyu Yi,Zhan Li,Jiayi Chen,Moshi Song,Yakun Zhang,Guang Xu,Qing Xia,Jun Gao,Tao Li,Kaiqing Wen,Teng Li,Chengcheng Yao,Jie Zhao,Tao Zhou,Zhaofang Bai,Xin Pan

doi:10.1038/s41467-022-28613-0

Abstract

Koolen-de Vries syndrome (KdVS) is a rare disorder caused by haploinsufficiency of KAT8 regulatory NSL complex subunit 1 (KANSL1), which is characterized by intellectual disability, heart failure, hypotonia, and congenital malformations. To date, no effective treatment has been found for KdVS, largely due to its unknown pathogenesis. Using siRNA screening, we identified KANSL1 as an essential gene for autophagy. Mechanistic study shows that KANSL1 modulates autophagosome-lysosome fusion for cargo degradation via transcriptional regulation of autophagosomal gene, STX17. Kansl1+/− mice exhibit impairment in the autophagic clearance of damaged mitochondria and accumulation of reactive oxygen species, thereby resulting in defective neuronal and cardiac functions. Moreover, we discovered that the FDA-approved drug 13-cis retinoic acid can reverse these mitophagic defects and neurobehavioral abnormalities in Kansl1+/− mice by promoting autophagosome-lysosome fusion. Hence, these findings demonstrate a critical role for KANSL1 in autophagy and indicate a potentially viable therapeutic strategy for KdVS.

Highlights

Koolen-de Vries syndrome (KdVS) is a rare disorder caused by haploinsufficiency of KAT8 regulatory NSL complex subunit 1 (KANSL1), which is characterized by intellectual disability, heart failure, hypotonia, and congenital malformations
It has long been established that KdVS is caused by the haploinsufficiency of KANSL1 gene[45], but little is known about the pathogenesis of this disease
In this study, using a Kansl[1] haploinsufficient mouse model, we provide evidence that the accumulation of damaged mitochondria caused by autophagic dysfunction is a previously unrecognized pathogenesis of KdVS

Summary

Introduction

Koolen-de Vries syndrome (KdVS) is a rare disorder caused by haploinsufficiency of KAT8 regulatory NSL complex subunit 1 (KANSL1), which is characterized by intellectual disability, heart failure, hypotonia, and congenital malformations. We discovered that the FDAapproved drug 13-cis retinoic acid can reverse these mitophagic defects and neurobehavioral abnormalities in Kansl1+/− mice by promoting autophagosome-lysosome fusion. These findings demonstrate a critical role for KANSL1 in autophagy and indicate a potentially viable therapeutic strategy for KdVS. We discover that an FDA-approved drug, 13-cis retinoic acid, promotes autophagosome-lysosome fusion and can reverse neurodegeneration in Kansl[1] heterozygous mice

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Results

Conclusion