Inhalt: Degeneration of sensory fibres is characteristic for hereditary sensory and autonomic neuropathies (HSANs). Affected patients share typical symptoms featured by a diminished sensation of temperature, touch and pain. However, the spectrum of disease-associated genes in patients is broad and frequently remains unclear. A previous study had shown that homozygous loss-of-function mutations of FAM134B are causative for severe HSAN classified as type 2B (HSAN2B). Within this thesis the pathophysiology of HSAN2B was addressed by analyzing transgenic Fam134b-knockout mice with biochemical approaches and cell culture assays. It was aimed to resolve the Fam134b protein localization, its topology, possible interaction partners and function. Fam134b-knockout mice manifested a progressive sensory neuropathy. Detailed analysis of sensory ganglion tissue sections of aged animals revealed ultrastructural alterations of the endoplasmic reticulum (ER) and Golgi cisternae by electron microscopy. Co immunoprecipitation studies demonstrated binding of FAM134B to autophagy-related ubiquitin-like proteins - also known as LC3-like modifiers or Atg8s. These interactions were mediated by the LC3-interacting region (LIR) that is conserved among members of the FAM134 protein family. Moreover, experiments addressing the topology of FAM134B showed that the C-terminally located LIR of FAM134B faces towards the cytoplasm and thus is accessible to various cytosolic proteins such as LC3. Overexpression studies in cell culture systems revealed FAM134B-mediated delivery of ER fragments into autophagosomal compartments, which was dependent on its functional LIR domain. Further, endogenous Fam134b protein expression was decreased under conditions of starvation. In conclusion, the data suggest that FAM134B serves as an ER-specific autophagy receptor. Hence, FAM134B may regulate ER turnover and maintain long-term homeostasis and survival especially of long-projecting sensory neurons.
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