Therapeutic Development in Segmental Demyelination

 描述(由申请人提供)： 脱髓鞘分流神经外的去极化电流。因此，动作电位的神经传导可以减慢甚至消除。后者称为传导阻滞。这种变化会导致神经功能障碍，如各种神经疾病中的感觉丧失、视力丧失和肢体瘫痪。我们发现，FIG4缺乏的患者和小鼠会患上脱髓鞘神经病。这种脱髓鞘密切地概括了获得性脱髓鞘疾病的特点。FIG4缺陷细胞表现出溶酶体膜分裂缺陷，溶酶体内钙离子通过溶酶体钙通道外流受到异常抑制。这些观察结果让我们提出了下面的假设。假设：FIG4缺乏使溶酶体膜上的钙通道失活，并阻止溶酶体释出钙离子。这反过来会损害溶酶体膜运输(溶酶体分裂缺陷)，导致节段性脱髓鞘。为此，我们提出以下具体目标。具体目的1.验证FIG4缺乏通过阻断髓鞘雪旺细胞溶酶体内钙离子外流而抑制溶酶体分裂的假说。具体目的2.确定雪旺细胞中FIG4缺乏是否会使该细胞对脱髓鞘敏感。为此，我们将利用图4条件基因敲除小鼠来研究图4-/-雪旺细胞中受损的溶酶体钙稳态如何使细胞对脱髓鞘敏感。具体目的3.验证髓鞘雪旺细胞中的FIG4是重新髓鞘形成所必需的假说。溶酶体膜转运在脱髓鞘/再髓鞘形成中的意义基本上是未知的。我们的结果表明，在FIG4缺乏的情况下，一条新的信号通路在溶酶体膜转运和脱髓鞘过程中似乎是关键的。由于图4-/-神经中的脱髓鞘概括了获得性脱髓鞘疾病的主要特征，该项目的结果也与其他获得性脱髓鞘疾病相关。此外，我们的初步结果表明，开发针对FIG4缺乏症脱髓鞘的治疗干预措施的可能性很高。

 DESCRIPTION (provided by applicant): Demyelination shunts depolarizing current out of the nerve. As a result, nerve conduction of action potentials can be slowed or even eliminated. The later is known as conduction block. This change causes neurological disabilities such as sensory loss, vision loss, and limb paralysis in a variety of neurological diseases. We have found that patients and mice with FIG4 deficiency develop a demyelinating neuropathy. This demyelination closely recapitulates features in acquired demyelinating diseases. The FIG4-deficient cells exhibit lysosomal membrane fission defect with an abnormally suppressed efflux of intralysosomal Ca2+ through a lysosomal Ca2+ channel. These observations lead us to propose the hypothesis below. Hypothesis: FIG4 deficiency deactivates Ca2+-channels on lysosomal membranes and prevents Ca2+ release from lysosomes. This, in turn, impairs lysosomal membrane trafficking (lysosomal fission defect), leading to segmental demyelination. Toward this end, we propose the following specific aims. Specific Aim 1. To test the hypothesis that FIG4 deficiency suppresses lysosomal fission by blocking the efflux of intralysosomal Ca2+ in myelinating Schwann cells. Specific Aim 2. To determine whether FIG4-deficiency in Schwann cell sensitizes the cell to demyelination. In this aim, we will utilize Fig4 conditional knockout mice to examine how the impaired lysosomal Ca2+-homeostasis in Fig4-/- Schwann cells may sensitize the cells to demyelination. Specific Aim 3. To test the hypothesis that FIG4 in myelinating Schwann cells is required for remyelination. Significance of lysosomal membrane trafficking in de/remyelination is essentially unexplored. Our results have demonstrated a novel signaling pathway in FIG4 deficiency that appears to be critical in lysosomal membrane trafficking and demyelination. Since demyelination in Fig4-/- nerves recapitulates key features of acquired demyelinating diseases, results from this project are also relevant to other acquired demyelinating disorders. Furthermore, our preliminary results suggest a high probability in developing therapeutic interventions for demyelination in FIG4 deficiency.