The established and emerging roles of astrocytes and microglia in amyotrophic lateral sclerosis and frontotemporal dementia.

Rowan A Radford,Dean L Pountney,Marco Morsch,Stephanie L Rayner,Nicholas J Cole,Roger S Chung

doi:10.3389/fncel.2015.00414

Rowan A Radford, Dean L Pountney + Show 4 more

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https://doi.org/10.3389/fncel.2015.00414

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Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two progressive, fatal neurodegenerative syndromes with considerable clinical, genetic and pathological overlap. Clinical symptoms of FTD can be seen in ALS patients and vice versa. Recent genetic discoveries conclusively link the two diseases, and several common molecular players have been identified (TDP-43, FUS, C9ORF72). The definitive etiologies of ALS and FTD are currently unknown and both disorders lack a cure. Glia, specifically astrocytes and microglia are heavily implicated in the onset and progression of neurodegeneration witnessed in ALS and FTD. In this review, we summarize the current understanding of the role of microglia and astrocytes involved in ALS and FTD, highlighting their recent implications in neuroinflammation, alterations in waste clearance involving phagocytosis and the newly described glymphatic system, and vascular abnormalities. Elucidating the precise mechanisms of how astrocytes and microglia are involved in ALS and FTD will be crucial in characterizing these two disorders and may represent more effective interventions for disease progression and treatment options in the future.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing multisystem neurodegenerative syndrome, characterized by the degeneration of the motor neurons (MNs) in the motor cortex, brainstem and spinal cord (Hardiman et al, 2011)
Abbreviations: ALS, Amyotrophic lateral sclerosis; Aβ, Amyloid beta; AQP4, Aquaporin 4; central nervous system (CNS), Central Nervous System; cerebrospinal fluid (CSF), Cerebrospinal Fluid; FTD, Frontotemporal dementia; fused in sarcoma (FUS), Fused in Sarcoma; GRN, Progranulin; iPSC, Inducible Pluripotent Stem Cell; MRI, Magnetic Resonance Imaging; MN, Motor Neuron; NF, κB, Nuclear Factorkappa B; OPTN, Optineurin; PET, Positron Emission Tomography; PFN1, Profilin 1; RNAi, RNA interference; SOD1, Superoxide Dismutase 1; SPECT, Single Positron Emission Computed Tomography; SQTSM1, Sequestosome 1; Tau, Microtubule Associated Protein Tau; TBK1, Tank Binding Kinase 1; TREM2, Triggering Receptor Expressed on Myeloid cells 2; TDP, 43-TAR DNA-binding 43; VCP, Valosin-Containing Protein
Research over the last decades has established that astrocytes and microglia play crucial roles in the development and/or progression of ALS and FTD through their complex interactions

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing multisystem neurodegenerative syndrome, characterized by the degeneration of the motor neurons (MNs) in the motor cortex, brainstem and spinal cord (Hardiman et al, 2011). Over the last 25 years, it has become increasingly apparent that ALS shares significant overlap with another progressive and fatal neurodegenerative syndrome Frontotemporal dementia (FTD). Up to 50% of patients with ALS develop FTD symptoms and approximately 15% of FTD patients display MN dysfunction typical of ALS (Ng et al, 2015). The causal mechanism/s of both syndromes are currently unknown and treatment is largely symptomatic (Hardiman et al, 2011; Piguet et al, 2011)

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