Elucidation of Relevant Neuroinflammation Mechanisms Using Gene Expression Profiling in Patients with Amyotrophic Lateral Sclerosis.
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.
Department of Physical Medicine and Rehabilitation, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, Korea.|Department of Medicine, the Graduate School of Yonsei University, Seoul, Korea.
Yu Hui
YH
Won
Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea.
Min-Young
MY
Lee
Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
Young-Chul
YC
Choi
Department of Neurosurgery, Spine & Spinal Cord Institute, College of Medicine, Yonsei University, Seoul, Korea.
Yoon
Y
Ha
Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.
Hyongbum
H
Kim
Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea.
Do-Young
DY
Kim
Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea.
Myung-Sun
MS
Kim
Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.
Ji Hea
JH
Yu
Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.
Jung Hwa
JH
Seo
Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.
MinGi
M
Kim
Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.
Sung-Rae
SR
Cho
Department of Rehabilitation Medicine, Gangnam Severance Hospital, Rehabilitation Institute of Neuromuscular Disease, Yonsei University College of Medicine, Seoul, Korea.|Department of Medicine, the Graduate School of Yonsei University, Seoul, Korea.
Seong-Woong
SW
Kang
D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications / Q000235:genetics*; D000818:Animals; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000150:complications; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged
D047908:Intracellular Signaling Peptides and Proteins; C410602:TOLLIP protein, human