Progranulin reduces insoluble TDP-43 levels, slows down axonal degeneration and prolongs survival in mutant TDP-43 mice

Sarah Herdewyn,Philip Van Damme,Matthieu Moisse,Ludo Van Den Bosch,Raheem Fazal,Wim Robberecht,Mathias De Decker,Sander Beel

doi:10.1186/s13024-018-0288-y

Sarah Herdewyn, Philip Van Damme + Show 6 more

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https://doi.org/10.1186/s13024-018-0288-y

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Abstract

BackgroundTAR DNA binding protein 43 (TDP-43) is the main disease protein in most patients with amyotrophic lateral sclerosis (ALS) and about 50% of patients with frontotemporal dementia (FTD). TDP-43 pathology is not restricted to patients with missense mutations in TARDBP, the gene encoding TDP-43, but also occurs in ALS/FTD patients without known genetic cause or in patients with various other ALS/FTD gene mutations. Mutations in progranulin (GRN), which result in a reduction of ~ 50% of progranulin protein (PGRN) levels, cause FTD with TDP-43 pathology. How loss of PGRN leads to TDP-43 pathology and whether or not PGRN expression protects against TDP-43-induced neurodegeneration is not yet clear.MethodsWe studied the effect of PGRN on the neurodegenerative phenotype in TDP-43(A315T) mice.ResultsPGRN reduced the levels of insoluble TDP-43 and histology of the spinal cord revealed a protective effect of PGRN on the loss of large axon fibers in the lateral horn, the most severely affected fiber pool in this mouse model. Overexpression of PGRN significantly slowed down disease progression, extending the median survival by approximately 130 days. A transcriptome analysis did not point towards a single pathway affected by PGRN, but rather towards a pleiotropic effect on different pathways.ConclusionOur findings reveal an important role of PGRN in attenuating mutant TDP-43-induced neurodegeneration.

Highlights

TAR DNA binding protein 43 (TDP-43) is the main disease protein in most patients with amyotrophic lateral sclerosis (ALS) and about 50% of patients with frontotemporal dementia (FTD)
Progranulin overexpression reduces insoluble TDP-43 levels in TDP-43(A315T) mice To study the therapeutic potential of human gene mutations. Mutations in progranulin (GRN) overexpression on TDP-43(A315T) induced neurodegeneration, TDP-43(A315T) mice, which express human mutant TDP-43 under the control of the prion promoter, were crossed with human GRN overexpressing mice, which carry a copy of human GRN cDNA in the ROSA26 locus resulting in human PGRN protein overexpression [39]
No significant changes in mouse Grn and the microglial marker Iba1 were observed in TDP-43(A315T) mice and PGRN overexpression did not influence the expression of these genes (Fig. 1c-d)

Summary

Introduction

TAR DNA binding protein 43 (TDP-43) is the main disease protein in most patients with amyotrophic lateral sclerosis (ALS) and about 50% of patients with frontotemporal dementia (FTD). Mutations in progranulin (GRN), which result in a reduction of ~ 50% of progranulin protein (PGRN) levels, cause FTD with TDP-43 pathology. How loss of PGRN leads to TDP-43 pathology and whether or not PGRN expression protects against TDP-43induced neurodegeneration is not yet clear. Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two related neurodegenerative disorders with overlapping molecular disease pathways. TAR DNA binding protein 43 (TDP-43) has been identified as an important disease protein for both ALS. The preferential expression of PGRN in neurons and activated microglia points towards its most important. PGRN ends up in late endosomes/lysosomes and facilitates the lysosomal clearance function [29], possibly by controlling the acidification of lysosomes [30] and by acting as a chaperone of degradation enzymes [31,32,33]

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