Astrocytes and Microglia as Potential Contributors to the Pathogenesis of C9orf72 Repeat Expansion-Associated FTLD and ALS.

Hannah Rostalski,Antti Cajanus,Anne M Remes,Kasper Katisko,Annakaisa Haapasalo,Stina Leskelä,Nadine Huber,Eino Solje,Teemu Natunen,Mikko Hiltunen,Mikael Marttinen

doi:10.3389/fnins.2019.00486

Abstract

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases with a complex, but often overlapping, genetic and pathobiological background and thus they are considered to form a disease spectrum. Although neurons are the principal cells affected in FTLD and ALS, increasing amount of evidence has recently proposed that other central nervous system-resident cells, including microglia and astrocytes, may also play roles in neurodegeneration in these diseases. Therefore, deciphering the mechanisms underlying the disease pathogenesis in different types of brain cells is fundamental in order to understand the etiology of these disorders. The major genetic cause of FTLD and ALS is a hexanucleotide repeat expansion (HRE) in the intronic region of the C9orf72 gene. In neurons, specific pathological hallmarks, including decreased expression of the C9orf72 RNA and proteins and generation of toxic RNA and protein species, and their downstream effects have been linked to C9orf72 HRE-associated FTLD and ALS. In contrast, it is still poorly known to which extent these pathological changes are presented in other brain cells. Here, we summarize the current literature on the potential role of astrocytes and microglia in C9orf72 HRE-linked FTLD and ALS and discuss their possible phenotypic alterations and neurotoxic mechanisms that may contribute to neurodegeneration in these diseases.

Highlights

Frontotemporal lobar degeneration (FTLD) is a group of neurodegenerative disorders affecting predominantly the frontal and temporal lobes of the brain (Gorno-Tempini et al, 2011; Rascovsky et al, 2011) and the second most prevalent early-onset dementia (Onyike and Diehl-Schmid, 2013)
Decreased levels of excitatory amino acid transporter (EAAT) 2 in the frontal cortex of FTLD patients compared to controls (Umoh et al, 2018) and in C9ALS compared to sporadic amyotrophic lateral sclerosis (ALS) patients (Fomin et al, 2018) suggest that astrocytes in both C9-hexanucleotide repeat expansion (HRE) carriers and non-carriers might show defective uptake of glutamate, which could lead to excitotoxicity
Antisense oligonucleotides targeting chromosome 9 open reading frame 72 (C9orf72) transcripts induced the mRNA levels of triggering receptor expressed on myeloid cells (TREM) 2, tyrosine kinase binding protein (TYROBP), C1q B chain (C1qb) and C3a receptor 1 (C3ar1), all predominantly expressed in microglia and regulating central microglial functions, including activation, pruning, and phagocytosis (Lagier-Tourenne et al, 2013), suggesting that reduced C9orf72 levels associate with alterations in these microglial functions

Summary

Introduction

Frontotemporal lobar degeneration (FTLD) is a group of neurodegenerative disorders affecting predominantly the frontal and temporal lobes of the brain (Gorno-Tempini et al, 2011; Rascovsky et al, 2011) and the second most prevalent early-onset dementia (Onyike and Diehl-Schmid, 2013). Levels of CD200, expressed on neurons and restricting microglial activation (Barclay et al, 2002), are reduced in the frontal cortex of FTLD compared to FTLD/ALS patients (Umoh et al, 2018).

Results

Conclusion