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Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease.

ABSTRACT: Dysregulation of autophagy, a cellular catabolic mechanism essential for degradation of misfolded proteins, has been implicated in multiple neurodegenerative diseases. However, the mechanisms that lead to the autophagy dysfunction are still not clear. Based on the results of a genome-wide screen, we show that reactive oxygen species (ROS) serve as common mediators upstream of the activation of the type III PI3 kinase, which is critical for the initiation of autophagy. Furthermore, ROS play an essential function in the induction of the type III PI3 kinase and autophagy in response to amyloid beta peptide, the main pathogenic mediator of Alzheimer's disease (AD). However, lysosomal blockage also caused by Abeta is independent of ROS. In addition, we demonstrate that autophagy is transcriptionally down-regulated during normal aging in the human brain. Strikingly, in contrast to normal aging, we observe transcriptional up-regulation of autophagy in the brains of AD patients, suggesting that there might be a compensatory regulation of autophagy. Interestingly, we show that an AD drug and an AD drug candidate have inhibitory effects on autophagy, raising the possibility that decreasing input into the lysosomal system may help to reduce cellular stress in AD. Finally, we provide a list of candidate drug targets that can be used to safely modulate levels of autophagy without causing cell death.

SUBMITTER: Lipinski MM

PROVIDER: S-EPMC2922576 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease.

Lipinski Marta M MM Zheng Bin B Lu Tao T Yan Zhenyu Z Py Bénédicte F BF Ng Aylwin A Xavier Ramnik J RJ Li Cheng C Yankner Bruce A BA Scherzer Clemens R CR Yuan Junying J

Proceedings of the National Academy of Sciences of the United States of America 20100726 32

Dysregulation of autophagy, a cellular catabolic mechanism essential for degradation of misfolded proteins, has been implicated in multiple neurodegenerative diseases. However, the mechanisms that lead to the autophagy dysfunction are still not clear. Based on the results of a genome-wide screen, we show that reactive oxygen species (ROS) serve as common mediators upstream of the activation of the type III PI3 kinase, which is critical for the initiation of autophagy. Furthermore, ROS play an es ...[more]

PMID: 20660724

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Project description:Macroautophagy (hereafter, autophagy) is a process that directs the degradation of cytoplasmic material in lysosomes. In addition to its homeostatic roles, autophagy undergoes dynamic positive and negative regulation in response to multiple forms of cellular stress, thus enabling the survival of cells. However, the precise mechanisms of autophagy regulation are not fully understood. To identify potential negative regulators of autophagy, we performed a genome-wide CRISPR screen using the quantitative autophagic flux reporter GFP-LC3-RFP. We identified phosphoribosylformylglycinamidine synthase, a component of the de novo purine synthesis pathway, as one such negative regulator of autophagy. Autophagy was activated in cells lacking phosphoribosylformylglycinamidine synthase or phosphoribosyl pyrophosphate amidotransferase, another de novo purine synthesis enzyme, or treated with methotrexate when exogenous levels of purines were insufficient. Purine starvation-induced autophagy activation was concomitant with mammalian target of rapamycin complex 1 (mTORC1) suppression and was profoundly suppressed in cells deficient for tuberous sclerosis complex 2, which negatively regulates mTORC1 through inhibition of Ras homolog enriched in brain, suggesting that purines regulate autophagy through the tuberous sclerosis complex-Ras homolog enriched in brain-mTORC1 signaling axis. Moreover, depletion of the pyrimidine synthesis enzymes carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase and dihydroorotate dehydrogenase activated autophagy as well, although mTORC1 activity was not altered by pyrimidine shortage. These results suggest a different mechanism of autophagy induction between purine and pyrimidine starvation. These findings provide novel insights into the regulation of autophagy by nucleotides and possibly the role of autophagy in nucleotide metabolism, leading to further developing anticancer strategies involving nucleotide synthesis and autophagy.

Project description:Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. However, the AD mechanism has not yet been fully elucidated to date, hindering the development of effective therapies. In our work, we perform a brain imaging genomics study to link genetics, single-cell gene expression data, tissue-specific gene expression data, brain imaging-derived volumetric endophenotypes, and disease diagnosis to discover potential underlying neurobiological pathways for AD. To do so, we perform brain-wide genome-wide colocalization analyses to integrate multidimensional imaging genomic biobank data. Specifically, we use (1) the individual-level imputed genotyping data and magnetic resonance imaging (MRI) data from the UK Biobank, (2) the summary statistics of the genome-wide association study (GWAS) from multiple European ancestry cohorts, and (3) the tissue-specific cis-expression quantitative trait loci (cis-eQTL) summary statistics from the GTEx project. We apply a Bayes factor colocalization framework and mediation analysis to these multi-modal imaging genomic data. As a result, we derive the brain regional level GWAS summary statistics for 145 brain regions with 482,831 single nucleotide polymorphisms (SNPs) followed by posthoc functional annotations. Our analysis yields the discovery of a potential AD causal pathway from a systems biology perspective: the SNP chr10:124165615:G>A (rs6585827) mutation upregulates the expression of BTBD16 gene in oligodendrocytes, a specialized glial cells, in the brain cortex, leading to a reduced risk of volumetric loss in the entorhinal cortex, resulting in the protective effect on AD. We substantiate our findings with multiple evidence from existing imaging, genetic and genomic studies in AD literature. Our study connects genetics, molecular and cellular signatures, regional brain morphologic endophenotypes, and AD diagnosis, providing new insights into the mechanistic understanding of the disease. Our findings can provide valuable guidance for subsequent therapeutic target identification and drug discovery in AD.

Dataset Information

Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease.

Publications

Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease.

Similar Datasets

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