Abstract
Since the discovery of the chromosome 9 open reading frame 72 (C9orf72) repeat expansion mutation in 2011 as the most common genetic abnormality in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) and frontotemporal dementia (FTD), progress in understanding the signaling pathways related to this mutation can only be described as intriguing. Two major theories have been suggested—(i) loss of function or haploinsufficiency and (ii) toxic gain of function from either C9orf72 repeat RNA or dipeptide repeat proteins (DPRs) generated from repeat-associated non-ATG (RAN) translation. Each theory has provided various signaling pathways that potentially participate in the disease progression. Dysregulation of the immune system, particularly glial cell dysfunction (mainly microglia and astrocytes), is demonstrated to play a pivotal role in both loss and gain of function theories of C9orf72 pathogenesis. In this review, we discuss the pathogenic roles of glial cells in C9orf72 ALS/FTD as evidenced by pre-clinical and clinical studies showing the presence of gliosis in C9orf72 ALS/FTD, pathologic hallmarks in glial cells, including TAR DNA-binding protein 43 (TDP-43) and p62 aggregates, and toxicity of C9orf72 glial cells. A better understanding of these pathways can provide new insights into the development of therapies targeting glial cell abnormalities in C9orf72 ALS/FTD.
Highlights
Amyotrophic lateral sclerosis (ALS, known as Lou Gehrig’s disease) and frontotemporal dementia (FTD) are two devastating neurodegenerative diseases with a high burden on society
Several PET studies have recently used radiotracers that bind to the 18 kD translocator protein (TSPO), a protein that is highly expressed on activated microglia and astrocytes, to track gliosis in amyotrophic lateral sclerosis (ALS) patients [198]
Since 2011 when the chromosome 9 open reading frame 72 (C9orf72) repeat expansion mutation was discovered as the most common genetic abnormality in familial ALS and FTD, an impressive number of studies have markedly improved our understanding of the pathologic mechanisms underlying the C9orf72 repeat expansion mutation
Summary
Amyotrophic lateral sclerosis (ALS, known as Lou Gehrig’s disease) and frontotemporal dementia (FTD) are two devastating neurodegenerative diseases with a high burden on society. In recent years, investigators have tried to elaborate a link between ALS/FTD gene mutations, including C9orf repeat expansions, and neuronal hyperexcitability/excitotoxicity mechanisms. The expression of kainate receptors and voltage-gated Ca2+ channels in iPSC-derived motor neurons, cell surface levels of the NMDA receptor GluN1 and the AMPA receptor GluR1 on neurites, and dendritic spines of iMNs from C9orf ALS/FTD patients are found to be markedly elevated compared to controls [34,52,53]. ADAR2 knockdown in mice motor neurons slows the rate of degeneration and reduces the loss of neuromuscular synapses in these cells [55] Agents such as an anticoagulation-deficient form of activated protein C (3K3A-APC), which can lower glutamate receptor levels, are able to decrease excitotoxicity and rescue proteostasis in vivo in both C9orf gain- and loss-of-function mouse models [56]
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