Temporospatial Analysis and New Players in the Immunology of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of lower and upper motor neurons (MN) leading to muscle weakness, paralysis and eventually death. Although a highly varied etiology results in ALS, it broadly manifests itself as sporadic and familial forms that have evident similarities in clinical symptoms and disease progression. There is a tremendous amount of knowledge on molecular mechanisms leading to loss of MNs and neuromuscular junctions (NMJ) as major determinants of disease onset, severity and progression in ALS. Specifically, two main opposing hypotheses, the dying forward and dying back phenomena, exist to account for NMJ denervation. The former hypothesis proposes that the earliest degeneration occurs at the central MNs and proceeds to the NMJ, whereas in the latter, the peripheral NMJ is the site of precipitating degeneration progressing backwards to the MN cell body. A large body of literature strongly indicates a role for the immune system in disease onset and progression via regulatory involvement at the level of both the central and peripheral nervous systems (CNS and PNS). In this review, we discuss the earliest reported immune responses with an emphasis on newly identified immune players in mutant superoxide dismutase 1 (mSOD1) transgenic mice, the gold standard mouse model for ALS.

Keywords: amyotrophic lateral sclerosis (ALS); immune response; motor neuron disease; neuroimmunology.

Figure 1

CD4+ T cells tip the balance between glial neurotrophism and neurotoxicity. Circulating CD4+ T cells (specifically, Tregs and Th2 cells) via yet-to-be identified mechanisms promote microglial and astrocyte production of trophic factors and anti-inflammatory cytokines. Depletion of CD4+ T cells in mSOD1 mice via different genetic approaches switches them to an activated proinflammatory phenotype with neurotoxic properties. BDNF: brain-derived neurotrophic factor; ER: endoplasmic reticulum; GDNF: glial cell-derived neurotrophic factor; ; IGF-1: insulin-like growth factor 1; IL-4: interleukin-4; MHC: major histocompatibility complex class I; mSOD1:mutant SOD1; NOX2: NADPH oxidase isoform 2; Tregs: regulatory T cells ; Th2: T helper 2; TCRβ: T cell receptor β; TGF-β: transforming growth factor-β; TNF-α: tumor necrosis factor-α.

Figure 2

A timeline of reported molecular, histological and functional events in the lifetime of mSOD1^G93A mice.

Figure 3

Schematic illustration summarizing peripheral nerve components and immune system involvement in degeneration and pathology.