Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by damage of motor neurons. Recent reports indicate that inflammatory responses occurring within the central nervous system contribute to the pathogenesis of ALS. We aimed to investigate disease-specific gene expression associated with neuroinflammation by conducting transcriptome analysis on fibroblasts from three patients with sporadic ALS and three normal controls. Several pathways were found to be upregulated in patients with ALS, among which the toll-like receptor (TLR) and NOD-like receptor (NLR) signaling pathways are related to the immune response. Genes—toll-interacting protein (TOLLIP), mitogen-activated protein kinase 9 (MAPK9), interleukin-1β (IL-1β), interleukin-8 (IL-8), and chemokine (C-X-C motif) ligand 1 (CXCL1)—related to these two pathways were validated using western blotting. This study validated the genes that are associated with TLR and NLR signaling pathways from different types of patient-derived cells. Not only fibroblasts but also induced pluripotent stem cells (iPSCs) and neural rosettes from the same origins showed similar expression patterns. Furthermore, expression of TOLLIP, a regulator of TLR signaling pathway, decreased with cellular aging as judged by changes in its expression through multiple passages. TOLLIP expression was downregulated in ALS cells under conditions of inflammation induced by lipopolysaccharide. Our data suggest that the TLR and NLR signaling pathways are involved in pathological innate immunity and neuroinflammation associated with ALS and that TOLLIP, MAPK9, IL-1β, IL-8, and CXCL1 play a role in ALS-specific immune responses. Moreover, changes of TOLLIP expression might be associated with progression of ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by damage of motor neurons, microglial activation, and wide astrogliosis in the motor cortex and spinal cord [1, 2]
From the confirmation of differentially expressed genes in normal- and patient-derived fibroblasts, this study demonstrated that the toll-like receptor (TLR) and NOD-like receptor (NLR) signaling pathways are involved in ALS pathogenesis and identified toll-interacting protein (TOLLIP), mitogen-activated protein kinase 9 (MAPK9), IL-1β, IL-8, and CXCL1
Inflammatory responses might play a vital role in the pathogenesis of motor neuron damage in ALS
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by damage of motor neurons, microglial activation, and wide astrogliosis in the motor cortex and spinal cord [1, 2]. Several genes associated with the disease have been identified; the pathogenic mechanisms are still elusive, and so far no curative therapeutic treatment has been developed. Suggested pathogenic mechanisms of ALS contain genetic factors, glutamate excitotoxicity, oxidative stress, weakened axonal transport, changed protein turnover, apoptosis, mitochondrial dysfunction, neurotrophic deficiency, and neuroinflammation [3]. Evidence accumulated over the past decade indicates that immune activation and inflammation might be implicated in ALS pathogenesis. Astrocytes, microglia, and immune-related cells have all been shown to be actively involved in ALS pathogenesis [2, 4,5,6,7,8]. The immune responses associated with neurodegenerative changes have been termed neuroinflammation. In pathologically affected areas of the central nervous system (CNS) in both human patients with ALS and mouse models of the disease, noticeable neuroinflammation can be observed [2]
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