ErbB4 Mutation that Decreased NRG1-ErbB4 Signaling Involved in the Pathogenesis of Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

Article type: Research Article

Authors: Sun, Lin^{a; 1} | Cheng, Baoying^{b; c; 1} | Zhou, Yuxun^{d; 1} | Fan, Yating^d | Li, Wei^a | Qiu, Qi^a | Fang, Yuan^a | Xiao, Shifu^{a; *} | Zheng, Honghua^{b; c; *} | Li, Xia^{a; *}

Affiliations: [a] Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China | [b] Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, China | [c] Department of Neuroscience, Shenzhen Research Institute of Xiamen University, Shenzhen, China | [d] The College of Chemistry, Chemical Engineering & Biotechnology, Donghua University, Shanghai, China

Correspondence: [*] Corresponding authors. Xia Li, PhD, No. 600 South Wanping Road, Xuhui Distinct, Shanghai, China. Tel.: +86 021 64387250; E-mail: [email protected]; Honghua Zheng, PhD, South Xiangan Road, Xiangan Distinct, Xiamen, China. Tel.: +860592 2880582; E-mail: [email protected]; Shifu Xiao, PhD, No. 600 South Wanping Road, Xuhui Distinct, Shanghai, China. Tel.: +86 021 64387250; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) includes a large spectrum of neurodegenerative disorders. Objective:To identify the relationship of ErbB4 mutation and ALS/FTD. Methods:Here, we report an atypical case of frontal variant behavioral abnormalities at the initial stage, a stable plateau stage of 5 years, and paralysis involving both upper and lower motor neurons followed by progressive cognitive dysfunction at the advanced stage. The clinical findings suggested a diagnosis of ALS/FTD, and genetic testing revealed erb-b2 receptor tyrosine kinase 4 (ErbB4) heterozygous mutation (c.2136 T>G, p.I712M), identified in an ALS pedigree previously. We modeled mutant ErbB4 protein through the SWISS-MODEL Server, and speculated on the structural change caused by the mutation. We also identified that ErbB4 (I712M) mutation led to reduced auto-phosphorylation of ErbB4 upon neuregulin-1 (NRG1) stimulation. Results:A functional analysis of ErbB4 mutation demonstrated an obviously decreased auto-phosphorylation of ErbB4 involving in the pathogenesis of ALS/FTD. Conclusion:We firstly found ErbB4 mutation to be identified in ALS/FTD.

Keywords: Amyotrophic lateral sclerosis, ErbB4, frontotemporal dementia, I712M, neuregulin-1

DOI: 10.3233/JAD-191230

Journal: Journal of Alzheimer's Disease, vol. 74, no. 2, pp. 535-544, 2020