한빛사논문
- 조회1,599
Wanlin Yanga,b,c,1, Kijung Sungb,1, Wei Xua, Maria J Rodriguezb,d, Andrew C. Wub, Sarai A. Santosb, Savannah Fangb, Rebecca K. Uberb, Stephanie X. Dongb, Brandon C. Guilloryb, Xavier Orainb, Jordan Rausb, Corrine Jolivaltd, Nigel Calcuttd, Robert A. Rissmanb,e, Jianqing Dinga, Chengbiao Wub,*
aDepartment of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
bDepartment of Neurosciences, University of California San Diego, La Jolla, CA, USA
cDepartment of Neurology, Zhuijiang Hospital, Southern Medical University, Guangzhou, China
dDepartment of Pathology, University of California San Diego, La Jolla, CA, USA
eVeterans Affairs San Diego Healthcare System, San Diego, CA, USA
1These authors contributed equally
*Corresponding author
Abstract
The R100W mutation in nerve growth factor is associated with hereditary sensory autonomic neuropathy V in a Swedish family. These patients develop severe loss of perception to deep pain but with apparently normal cognitive functions. To better understand the disease mechanism, we examined a knockin mouse model of HSAN V. The homozygous mice showed significant structural deficits in intra-epidermal nerve fibers (IENFs) at birth. These mice had a total loss of pain perception at ∼2 months of age and often failed to survive to adulthood. Heterozygous mutant mice developed a progressive degeneration of small sensory fibers both behaviorally and functionally: they showed a progressive loss of IENFs starting at the age of 9 months accompanied with progressive loss of perception to painful stimuli such as noxious temperature. Quantitative analysis of lumbar 4/5 dorsal root ganglia revealed a significant reduction in small size neurons, while analysis of sciatic nerve fibers revealed the heterozygous mutant mice had no reduction in myelinated nerve fibers. Significantly, the amount of NGF secreted from mouse embryonic fibroblasts were reduced from both heterozygous and homozygous mice compared to their wild-type littermates. Interestingly, the heterozygous mice showed no apparent structural alteration in the brain: neither the anterior cingulate cortex nor the medial septum including NGF-dependent basal forebrain cholinergic neurons. Accordingly, these animals did not develop appreciable deficits in tests for brain function. Our study has thus demonstrated that the NGFR100W mutation likely affects the structure and function of peripheral sensory neurons.
Keywords : Hereditary Sensory Autonomic Neuropathy V; Knockin Mouse Model; Pain; Nerve Growth Factor; TrkA; p75 neutrophic factor receptor; Nociception; Cognition; Intraepidermal Nerve Fiber; Dorsal Root Ganglion
논문정보
- Research article
- 2020년 07월 (BRIC 등록일 2020-07-27)
- 국외 연구진
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