Section of Molecular Cell and Developmental Biology, Institute for Cell and Molecular Biology, Institute for Neuroscience, University of Texas at Austin, Austin, Texas 78712, USA.
J Comp Neurol. 2012 Jun 1;520(8):1751-71. doi: 10.1002/cne.23011.
Spinal cord injury axotomizes neurons and induces many of them to die, whereas others survive. Therefore, it is important to identify factors that lead to neuronal death after injury as a first step toward developing better strategies for increasing neuronal survival and functional recovery. However, the intrinsic molecular pathways that govern whether an injured neuron lives or dies remain surprisingly unclear. To address this question, we took advantage of the large size of giant reticulospinal (RS) neurons in the brain of the lamprey, Petromyzon marinus. We report that axotomy of giant RS neurons induces a select subset of them to accumulate high levels of synuclein, a synaptic vesicle-associated protein whose abnormal accumulation is linked to Parkinson's disease. Injury-induced synuclein accumulation occurred only in neurons that were classified as "poor survivors" by both histological and Fluoro-Jade C staining. In contrast, post-injury synuclein immunofluorescence remained at control levels in neurons that were identified as "good survivors." Synuclein accumulation appeared in the form of aggregated intracellular inclusions. Cells that accumulated synuclein also exhibited more ubiquitin-containing inclusions, similar to what occurs during disease states. When synuclein levels and cell vitality were measured in the same neurons, it became clear that synuclein accumulation preceded and strongly correlated with subsequent neuronal death. Thus, synuclein accumulation is identified as a marker and potential risk factor for forthcoming neuronal death after axotomy, expanding its implications beyond the neurodegenerative diseases.
脊髓损伤会使神经元轴突断裂，并导致其中许多神经元死亡，而其他神经元则存活下来。因此，确定损伤后导致神经元死亡的因素是开发更好的增加神经元存活和功能恢复策略的第一步。然而，支配受伤神经元生死的内在分子途径仍然令人惊讶地不清楚。为了解决这个问题，我们利用了七鳃鳗大脑中巨大的网状脊髓（RS）神经元的巨大尺寸。我们报告说，巨大 RS 神经元的轴突切断会导致其中一部分神经元积累高水平的突触核蛋白，突触核蛋白是一种与帕金森病有关的突触小泡相关蛋白。损伤诱导的突触核蛋白积累仅发生在通过组织学和荧光素-Jade C 染色被分类为“差生存者”的神经元中。相比之下，在被鉴定为“良好生存者”的神经元中，损伤后的突触核蛋白免疫荧光仍保持在对照水平。突触核蛋白积累以细胞内聚集物的形式出现。积累突触核蛋白的细胞还表现出更多含有泛素的包含物，类似于在疾病状态下发生的情况。当在相同的神经元中测量突触核蛋白水平和细胞活力时，很明显突触核蛋白的积累先于随后的神经元死亡，并与神经元死亡强烈相关。因此，突触核蛋白积累被鉴定为轴突切断后即将发生的神经元死亡的标志物和潜在风险因素，其意义超出了神经退行性疾病。
