Therapeutic Development in Segmental Demyelination

 描述（由申请人提供）： 脱髓鞘使去极化电流从神经中分流出来。因此，动作电位的神经传导可以减慢甚至消除。后者被称为传导阻滞。这种变化会导致神经功能障碍，如各种神经系统疾病中的感觉丧失、视力丧失和肢体瘫痪。 我们发现FIG 4缺陷的患者和小鼠发生脱髓鞘性神经病。这种脱髓鞘紧密地概括了获得性脱髓鞘疾病的特征。FIG 4缺陷细胞表现出溶酶体膜分裂缺陷，伴有溶酶体内Ca 2+通过溶酶体Ca 2+通道的流出异常受抑制。这些观察使我们提出下面的假设。假设：FIG 4缺乏使溶酶体膜上的Ca 2+通道失活并阻止Ca 2+从溶酶体释放。这反过来又损害了溶酶体膜运输（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。具体目标1。为了检验FIG 4缺陷通过阻断髓鞘化雪旺细胞中溶酶体内Ca 2+的流出来抑制溶酶体分裂的假设。具体目标2。确定雪旺细胞中FIG 4-缺陷是否使细胞对脱髓鞘敏感。在这个目标中，我们将利用Fig 4条件性敲除小鼠来检查Fig 4-/-雪旺细胞中受损的溶酶体Ca 2+稳态如何使细胞对脱髓鞘敏感。具体目标3。为了检验髓鞘形成施旺细胞中的FIG 4是髓鞘再生所需的假设。 溶酶体膜运输在脱髓鞘/髓鞘再生中的意义基本上未被探索。我们的研究结果已经证明了FIG 4缺陷中的一种新的信号传导途径，该途径似乎在溶酶体膜运输和脱髓鞘中至关重要。由于Fig 4-/-神经中的脱髓鞘概括了获得性脱髓鞘疾病的关键特征，因此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，在FIG 4缺陷中开发脱髓鞘的治疗干预的可能性很高。

 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.