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

周围神经病变影响数百万人的生活质量。在这里，主要是小的感觉周围神经纤维的变性导致慢性疼痛感知障碍，并被称为小纤维神经病（SFN）。在遗传性感觉和自主神经病（HSAN）中，中型和大型神经纤维也受到影响。有趣的是，这些形式的神经病变通常是由内质网（ER）的结构膜蛋白突变引起的，其中包括这里研究的atlastins（ATLs）。三种同源ATL（ATL 1、ATL 2和ATL 3）是控制多边形ER网络的组装和重塑的大GTP酶。我们首次证明了ATL 1和ATL 3的突变是致病的，并导致感觉神经纤维变性的单基因形式。我们现在有证据表明，ATL 2的某些变体也会导致SFN。该项目将使用各种遗传学，细胞生物学，生物化学和神经病理学方法对这一新发现进行研究，从而详细解释ATL 2疾病的机制。我们将特别注意ER的选择性自噬（ER-吞噬），这是一个最近描述的控制ER不断重塑的过程，允许有丝分裂后感觉神经元的长期存活。我们以前确定了第一个触发选择性ER-吞噬的自噬受体，随后还描述了ATL蛋白参与ER-吞噬。此外，一般自噬，毒性聚集体和异常异二聚体形成，以及受损的轴突运输由于ATL突变的干扰正在调查中。我们的研究还将扩展到ATL 1和ATL 3突变，以了解ATL功能的特定差异和共性。细胞结果将在ATL 1 -3突变患者的神经和皮肤活检中进行验证。最后，我们正在利用这些结果，通过使用下一代测序技术，在我们独特的10，000多个人类皮肤和12，000个人类神经样本的组织生物库中确定轴突“ER病变”的其他未知遗传原因。

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.