Clearance of peripheral nerve misfolded mutant protein by infiltrated macrophages correlates with motor neuron disease progression

Abstract

Macrophages expressing C–C chemokine receptor type 2 (CCR2) infiltrate the central and peripheral neural tissues of amyotrophic lateral sclerosis (ALS) patients. To identify the functional role of CCR2+ macrophages in the pathomechanisms of ALS, we used an ALS animal model, mutant Cu/Zn superoxide dismutase 1G93A (mSOD1)-transgenic (Tg) mice. To clarify the CCR2 function in the model, we generated SOD1G93A/CCR2Red fluorescence protein (RFP)/Wild type (WT)/CX3CR1Green fluorescence protein (GFP)/WT-Tg mice, which heterozygously express CCR2-RFP and CX3CR1-GFP, and SOD1G93A/CCR2RFP/RFP-Tg mice, which lack CCR2 protein expression and present with a CCR2-deficient phenotype. In mSOD1-Tg mice, mSOD1 accumulated in the sciatic nerve earlier than in the spinal cord. Furthermore, spinal cords of SOD1G93A/CCR2RFP/WT/CX3CR1GFP/WT mice showed peripheral macrophage infiltration that emerged at the end-stage, whereas in peripheral nerves, macrophage infiltration started from the pre-symptomatic stage. Before disease onset, CCR2+ macrophages harboring mSOD1 infiltrated sciatic nerves earlier than the lumbar cord. CCR2-deficient mSOD1-Tg mice showed an earlier onset and axonal derangement in the sciatic nerve than CCR2-positive mSOD1-Tg mice. CCR2-deficient mSOD1-Tg mice showed an increase in deposited mSOD1 in the sciatic nerve compared with CCR2-positive mice. These findings suggest that CCR2+ and CX3CR1+ macrophages exert neuroprotective functions in mSOD1 ALS via mSOD1 clearance from the peripheral nerves.

Misfolding at the synapse: A role in amyotrophic lateral sclerosis pathogenesis?

“…Immunoblots of sciatic nerves have shown mutant SOD1 aggregates (Turner et al, 2003), indicating their presence in axo-synaptic compartments. In line with this, mutant SOD1 accumulation has been observed in ventral roots as early as four weeks of age, before their presence within the ventral horn and onset of motor impairment (Shiraishi et al, 2021). This indicates mutant SOD1 may accumulate in a distal-proximal fashion.…”

Neuroimmune Crosstalk Between the Peripheral and the Central Immune System in Amyotrophic Lateral Sclerosis

“…In addition, monocyte-derived macrophages are activated in ALS. Activated macrophages exert neuroprotective functions by misfolding protein clearance during the disease ( Chiu et al, 2009 ; Shiraishi et al, 2021 ). Macrophages also showed limited infiltration to the CNS.…”

Macrophage-Targeted Sodium Chlorite (NP001) Slows Progression of Amyotrophic Lateral Sclerosis (ALS) through Regulation of Microbial Translocation

“…Recent machine learning approaches using a genetic model of ALS (G93A SOD-1 mutant) have identified what might be the very earliest abnormalities in ALS pathogenesis [ 11 , 12 , 13 ]. Rather than the disease being initiated within the affected motor neuron body, the initial site of disease onset has been mapped to the distal axonic processes within the neuromuscular junction.…”

“…Rather than the disease being initiated within the affected motor neuron body, the initial site of disease onset has been mapped to the distal axonic processes within the neuromuscular junction. The G93A ALS model has a mutant form of SOD-1; the earliest site of abnormal immune-mediated disease activity associated with this molecule is within the axonic processes and damage associated with the molecule is mediated by blood-derived macrophages [ 12 , 13 ]. In one study, a mutation of the macrophage “respiratory burst” gene, NADPH oxidase, led to a slowing of the disease [ 11 ].…”