A Variant of the Autophagy-Related 5 Gene Is Associated with Child Cerebral Palsy

Xu, Jianhua; Xia, Lei; Shang, Qing; Du, Jing; Zhu, Dengna; Wang, Yangong; Bi, Dingren; Shi, Juan; Ma, Caiyun; Gao, Chao; Zhang, Xiaoli; Sun, Yanyan; Zhu, Ling‐Ling; Wang, Xiaoyang; Zhu, Changlian; Xing, Qinghe

doi:10.3389/fncel.2017.00407

Cited by 30 publications

(29 citation statements)

References 49 publications

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“…These data suggest that the reduction of autophagic flux in these patients might be due to defective lipidation of ATG8 family proteins . Recently, a polymorphism of ATG5 (rs6568431) correlated with lower ATG5 expression was associated with childhood cerebral palsy (CP) . However, the detailed mechanism about how this polymorphism causes CP has not been reported.…”

Section: Hereditary Childhood Ataxiasmentioning

confidence: 99%

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Autophagy in childhood neurological disorders

Zhu¹,

Runwal²,

Obrocki³

et al. 2018

Develop Med Child Neuro

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Autophagy is a tightly modulated lysosomal degradation pathway. Genetic disorders of autophagy during nervous system development may lead to developmental delay, neurodegeneration, and other neurological signs in children. Here we aimed to summarize single gene disorders that perturb various steps of autophagy pathway and their roles in the causation of childhood neurological diseases. Numerous childhood‐onset disorders are caused by mutations that impact the autophagy pathway. These can manifest with a range of features including ataxia, spastic paraplegia, and intellectual disability. Defective proteins causing such diseases can interfere with autophagy flux at different stages of the itinerary. Defective autophagy may be an important contributor to the pathological features of various childhood neurodegenerative diseases and lead to the accumulation of aberrant protein and dysfunctional organelles. Insights into the relevant cell biological processes may help understand pathophysiological mechanisms and inspire autophagy‐restoring therapeutic approaches. What this paper adds Numerous childhood‐onset disorders are caused by mutations that impact the autophagy pathway. Defective autophagy is a feature of some mutations that cause ataxia, spastic paraplegia, and intellectual disability.

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Section: Hereditary Childhood Ataxiasmentioning

confidence: 99%

“…1,8 Recently, a polymorphism of ATG5 (rs6568431) correlated with lower ATG5 expression was associated with childhood cerebral palsy (CP). 9 However, the detailed mechanism about how this polymorphism causes CP has not been reported. Review 641…”

Section: Hereditary Childhood Ataxiasmentioning

confidence: 99%

Autophagy in childhood neurological disorders

Zhu¹,

Runwal²,

Obrocki³

et al. 2018

Develop Med Child Neuro

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“…11 In humans, mutations or polymorphisms in autophagy genes are associated with susceptibility to infection, cancer, inflammatory diseases, asthma, cerebral palsy, frontotemporal dementia, amyotrophic lateral sclerosis (ALS), Huntington’s disease, and Parkinson’s disease. 11–14 Moreover, gain-of-function mutations or enforced expression of autophagy genes in mice have beneficial effects including improved metabolism and tissue function, extended lifespan, neuroprotection, and decreased tumorigenesis. 11, 15–19 Thus, the development of autophagy-inducing agents may be a promising therapeutic approach to prevent and/or treat certain diseases in clinical medicine.…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Screens To Identify Autophagy Inducers That Function by Disrupting Beclin 1/Bcl-2 Binding

et al. 2018

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Autophagy, a lysosomal degradation pathway, plays a crucial role in cellular homeostasis, development, immunity, tumor suppression, metabolism, prevention of neurodegeneration and lifespan extension. Thus, pharmacological stimulation of autophagy may be an effective approach for preventing or treating certain human diseases and/or aging. We sought to establish a method for developing new chemical compounds that specifically induce autophagy. To do this, we developed two assays to identify compounds that target a key regulatory node of autophagy induction – specifically, the binding of Bcl-2 (a negative regulator of autophagy) to Beclin 1 (an allosteric modulator of the Beclin 1/VPS34 lipid kinase complex that functions in autophagy initiation). These assays use either a split-luciferase assay to measure Beclin 1/Bcl-2 binding in cells or an AlphaLISA assay to directly measure direct Beclin 1/Bcl-2 binding in vitro. We screened two different chemical compound libraries, comprising ~300K compounds, to identify small molecules that disrupt Beclin 1/Bcl-2 binding and induce autophagy. Three novel compounds were identified that directly inhibit Beclin 1/Bcl-2 interaction with an IC50 in the micromolar range and increase autophagic flux. These compounds do not demonstrate significant cytotoxicity and they exert selectivity for disruption of Bcl-2 binding to the BH3 domain of Beclin 1 compared to the BH3 domain of the pro-apoptotic Bcl-2 family members, Bax and Bim. Thus, we have identified candidate molecules that serve as lead templates for developing potent and selective Beclin 1/Bcl-2 inhibitors that may be clinically useful as autophagy-inducing agents.

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“…SNPs and variants causing dysregulation of ATG5 expression levels have also been reported. A homozygous ATG5 variant (rs6568431 AA genotype) resulting in lower ATG5 expression was identified to be associated with childhood cerebral palsy (CP) 20 . It will be important to validate these findings in subsequent replication studies.…”

Section: Dysfunction Of the Cerebellar Vermis Causes Staggeringmentioning

confidence: 99%

Mendelian neurodegenerative disease genes involved in autophagy

et al. 2020

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The lysosomal degradation pathway of macroautophagy (herein referred to as autophagy) plays a crucial role in cellular physiology by regulating the removal of unwanted cargoes such as protein aggregates and damaged organelles. Over the last five decades, significant progress has been made in understanding the molecular mechanisms that regulate autophagy and its roles in human physiology and diseases. These advances, together with discoveries in human genetics linking autophagy-related gene mutations to specific diseases, provide a better understanding of the mechanisms by which autophagy-dependent pathways can be potentially targeted for treating human diseases. Here, we review mutations that have been identified in genes involved in autophagy and their associations with neurodegenerative diseases. LC3/GABARAP family protein lipidation. The core ATG proteins are necessary, but not sufficient for degradative autophagy (Fig. 1). Autophagosomal degradation cannot proceed without successful fusion to functional lysosomes. Research in the past decade has unmasked several key factors required for autophagolysosomal fusion, such as the GABARAP subfamily, as well as the CORVET-HOPS and the STX17-SNAP29-VAMP8/ VAMP7 SNARE complexes 2-5 .

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A Variant of the Autophagy-Related 5 Gene Is Associated with Child Cerebral Palsy

Cited by 30 publications

References 49 publications

Autophagy in childhood neurological disorders

Autophagy in childhood neurological disorders

High-Throughput Screens To Identify Autophagy Inducers That Function by Disrupting Beclin 1/Bcl-2 Binding

Mendelian neurodegenerative disease genes involved in autophagy

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