ATL gene family: How mutations in ER-shaping proteins cause axonopathy

周围神经病影响着数百万人的生活质量。在这里，以小感觉神经纤维为主的退行性变导致慢性痛觉障碍，被称为小纤维神经病(SFN)。在遗传性感觉神经病和自主神经病(HSAN)中，中等和大型神经纤维也会受到影响。有趣的是，这些形式的神经病变通常是由内质网(ER)结构膜蛋白的突变引起的，其中包括本文研究的atlastins(ATLS)。三个同源的ATL(ATL1、ATL2和ATL3)是控制多边形ER网络的组装和重塑的大GTP酶。我们首次证明ATL1和ATL3的突变都是致病的，并导致单基因形式的感觉神经纤维变性。我们现在有证据表明，ATL2的某些变异也可以导致SFN。这一新发现将在该项目中使用各种遗传学、细胞生物学、生化和神经病理学方法进行调查，从而详细破译ATL2疾病的机制。我们将特别关注内质网的选择性自噬(内质网吞噬)，这是最近描述的一个过程，控制内质网的持续重塑，允许有丝分裂后感觉神经元的长期生存。我们以前发现了第一个触发选择性ER吞噬的自噬受体，随后也描述了ATL蛋白在ER吞噬中的作用。此外，由于ATL突变引起的一般自噬、毒性聚合体和异源二聚体形成的障碍，以及轴突运输受损的研究正在进行中。我们的研究还将扩展到ATL1和ATL3突变，以了解ATL功能的特定差异和共性。细胞发现将在ATL1-3突变患者的神经和皮肤活检中得到翻译验证。最后，我们正在利用这一结果，通过使用下一代测序技术，在我们独特的组织生物库中确定轴突“内质网病变”的其他未知遗传原因，该组织生物库包含10,000多个人类皮肤和12,000个人类神经样本。

Peripheral neuropathies affect the quality of life of millions of people. Here, the degeneration of predominantly small sensory peripheral nerve fibers leads to chronic disorders of pain perception and is referred to as Small Fiber Neuropathy (SFN). In Hereditary Sensory and Autonomic Neuropathies (HSAN), medium and large nerve fibers are also affected. Interestingly, these forms of neuropathy are often caused by mutations in structural membrane proteins of the endoplasmic reticulum (ER), which include the atlastins (ATLs) studied here. The three homologous ATLs (ATL1, ATL2, and ATL3) are large GTPases that control the assembly and remodelling of the polygonal ER network. We have shown for the first time that mutations in both ATL1 and ATL3 are disease-causing and lead to monogenic forms of sensory nerve fiber degeneration. We now have evidence that certain variants in ATL2 can also cause SFN. This new finding will be investigated in the project using a variety of genetic, cell biological, biochemical and neuropathological methods and the mechanism of the ATL2 disease will thereby be deciphered in detail. We will pay particular attention to selective autophagy of the ER (ER-phagy), a recently described process that controls constant remodelling of the ER, allowing long-term survival of postmitotic sensory neurons. We previously identified the first autophagy receptor triggering selective ER-phagy and subsequently the involvement of ATL proteins in ER-phagy was also described. In addition, disturbances of general autophagy, toxic aggregate- and abnormal heterodimer formation, and impaired axonal transport due to ATL-mutations are being investigated. Our studies will also be extended to ATL1 and ATL3 mutations to understand specific differences and commonalities in ATL function. Cellular findings will be translationally verified in nerve and skin biopsies from patients with ATL1-3 mutations. Finally, we are using the results to identify additional unknown genetic causes of axonal "ER-pathies" in our unique tissue biobank of over 10,000 human skin and 12,000 human nerve samples and by using next-generation sequencing technologies.