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

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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.