Granulins Regulate Aging Kinetics in the Adult Zebrafish Telencephalon.

Alessandro Zambusi,Rossella Di Giaimo,Jovica Ninkovic,Özge Pelin Burhan,Bettina Schmid

doi:10.3390/cells9020350

Abstract

Granulins (GRN) are secreted factors that promote neuronal survival and regulate inflammation in various pathological conditions. However, their roles in physiological conditions in the brain remain poorly understood. To address this knowledge gap, we analysed the telencephalon in Grn-deficient zebrafish and identified morphological and transcriptional changes in microglial cells, indicative of a pro-inflammatory phenotype in the absence of any insult. Unexpectedly, activated mutant microglia shared part of their transcriptional signature with aged human microglia. Furthermore, transcriptome profiles of the entire telencephali isolated from young Grn-deficient animals showed remarkable similarities with the profiles of the telencephali isolated from aged wildtype animals. Additionally, 50% of differentially regulated genes during aging were regulated in the telencephalon of young Grn-deficient animals compared to their wildtype littermates. Importantly, the telencephalon transcriptome in young Grn-deficent animals changed only mildly with aging, further suggesting premature aging of Grn-deficient brain. Indeed, Grn loss led to decreased neurogenesis and oligodendrogenesis, and to shortening of telomeres at young ages, to an extent comparable to that observed during aging. Altogether, our data demonstrate a role of Grn in regulating aging kinetics in the zebrafish telencephalon, thus providing a valuable tool for the development of new therapeutic approaches to treat age-associated pathologies.

Highlights

Aging is associated with numerous changes in a wide range of processes, progressively leading to impaired organ function and increasing the risk of the onset of numerous pathologies
Granulin is a key factor mainly expressed in microglia and neurons that is involved in the regulation of several processes including inflammation in the mouse cerebral cortex [38,39]
Despite numerous studies performed in the context of neurodegeneration and wound healing that have revealed the association of GRN with various processes including wound healing, inflammation, lysosome regulation, neuronal survival, and neurodegeneration [86,87], the physiological roles of GRN in the central nervous system (CNS) remain elusive

Summary

Introduction

Aging is associated with numerous changes in a wide range of processes, progressively leading to impaired organ function and increasing the risk of the onset of numerous pathologies. Brain aging is one of the greatest risk factors for multifactorial diseases including Alzheimer’s and Parkinson’s diseases [1] Typical aging hallmarks such as genomic instability, telomere shortening, metabolic dysregulation, cellular senescence, stem cell exhaustion, and decreased neurogenesis are observed in the brain and affect a broad range of cellular functions [2], thereby leading to impaired tissue homeostasis and regeneration. One major challenge is to better understand the relationship among these processes in different cell types and to identify novel pathways and regulators contributing to aging regulation These pathways would be suitable targets for the development of new therapeutic approaches aiming to limit or block the detrimental phenotypes acquired with aging, decreasing the risk of associated pathologies

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Conclusion