Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA; Department of Neurology, Zhuijiang Hospital, Southern Medical University, Guangzhou, China.
Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
Prog Neurobiol. 2020 Nov;194:101886. doi: 10.1016/j.pneurobio.2020.101886. Epub 2020 Jul 18.
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 NGF mutation likely affects the structure and function of peripheral sensory neurons.
神经生长因子 R100W 突变与瑞典一个家族的遗传性感觉自主神经病 V 相关。这些患者表现为严重的深部痛觉丧失，但认知功能似乎正常。为了更好地了解疾病的机制，我们研究了 HSAN V 的基因敲入小鼠模型。纯合子小鼠在出生时就表现出表皮内神经纤维（IENFs）的显著结构缺陷。这些小鼠在大约 2 个月大时就完全丧失了痛觉，而且往往无法存活到成年。杂合突变小鼠在行为和功能上都表现出小感觉纤维的进行性退化：它们在 9 个月大时开始出现 IENFs 的进行性丧失，伴随着对有害温度等疼痛刺激的感知逐渐丧失。对腰椎 4/5 背根神经节的定量分析显示，小尺寸神经元明显减少，而对坐骨神经纤维的分析显示，杂合突变小鼠的有髓神经纤维没有减少。值得注意的是，与野生型同窝仔相比，从杂合和纯合突变的小鼠胚胎成纤维细胞中分泌的 NGF 减少。有趣的是，杂合突变小鼠的大脑没有明显的结构改变：无论是扣带前皮质还是内侧隔核，包括 NGF 依赖的基底前脑胆碱能神经元。因此，这些动物在大脑功能测试中没有出现明显的缺陷。我们的研究表明，NGF 突变可能影响外周感觉神经元的结构和功能。
