Analysis of the Biomarkers for Neurodegenerative Diseases in Aged Progranulin Deficient Mice.

Xiangli Zhao,Chuanju Liu,Ying Sun,Yi Lin,Sadaf Hasan,Benjamin Liou

doi:10.3390/ijms23020629

Abstract

Neurodegenerative diseases are debilitating impairments that affect millions of people worldwide and are characterized by progressive degeneration of structure and function of the central or peripheral nervous system. Effective biomarkers for neurodegenerative diseases can be used to improve the diagnostic workup in the clinic as well as facilitate the development of effective disease-modifying therapies. Progranulin (PGRN) has been reported to be involved in various neurodegenerative disorders. Hence, in the current study we systematically compared the inflammation and accumulation of typical neurodegenerative disease markers in the brain tissue between PGRN knockout (PGRN KO) and wildtype (WT) mice. We found that PGRN deficiency led to significant neuron loss as well as activation of microglia and astrocytes in aged mice. Several characteristic neurodegenerative markers, including α-synuclein, TAR DNA-binding protein 43 (TDP-43), Tau, and β-amyloid, were all accumulated in the brain of PGRN-deficient mice as compared to WT mice. Moreover, higher aggregation of lipofuscin was observed in the brain tissue of PGRN-deficient mice compared with WT mice. In addition, the autophagy was also defective in the brain of PGRN-deficient mice, indicated by the abnormal expression level of autophagy marker LC3-II. Collectively, comprehensive assays support the idea that PGRN plays an important role during the development of neurodegenerative disease, indicating that PGRN might be a useful biomarker for neurodegenerative diseases in clinical settings.

Highlights

Neurodegenerative diseases have become a growing threat to human health
The heterozygous mutation of GRN leads to haploinsufficiency of PGRN, which is the major cause of frontotemporal dementia (FTD), characterized by the aggregates of ubiquited-protein in TDP-43 [9]
PGRN haploinsufficiency is associated with neurodegenerative diseases and is widely studied in FTLD and neuronal ceroid lipofuscinosis (NCL)

Summary

Introduction

Neurodegenerative diseases have become a growing threat to human health. Examples of neurodegenerative diseases are Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease and frontotemporal dementia (FTD). [1]. The landmark study about the involvement of PGRN in neurodegenerative disease showed its association with FTD in 2006 [9]. The homozygous GRN mutations result in neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease [10]. The abnormalities in the CNS of Grn−/− mouse models facilitate the understanding of PGRN’s role in neurodegenerative diseases. In addition to the link of Grn’s mutation to the development of FTD and NCL, PGRN represents a protective role in the growth and development of neurons in various animal models [16]. Gene delivery of PGRN exhibits protective effects on dopaminergic neurons and improves lysosomal dysfunction and microglial pathology in a mouse model of PD, FTD and NCL [17,18,19]. PGRN is a well-established regulator of autophagy [20,21,22]

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Results

Conclusion