When the cell digests itself: How inherited neurodegenerative diseases develop

Newswise — FRANKFURT. A maze of pouches, ducts, and sack-like membrane systems traverses the cells of humans, animals, plants, and fungi: the endoplasmic reticulum, or ER for brevity. Within the ER, proteins are crafted, shaped into their three-dimensional form, and altered, while lipids and hormones are generated, and cellular calcium levels are regulated. Moreover, the ER serves as the foundation for the cell's transportation system, dispatches misfolded proteins for intracellular disposal, and neutralizes toxins that have infiltrated the cell.

Due to its myriad functions, the ER experiences constant remodeling. ER-phagy, coined as "ER self-digestion," plays a vital role in ER degradation. This process relies on a set of signal-receiving proteins, or receptors, that govern the ER's membrane curvatures, thereby shaping its diverse forms within the cell. In ER-phagy, these receptors accumulate at precise ER sites, triggering a substantial augmentation in membrane curvature. As a result, a segment of the ER becomes constricted and disassembled into its constituent components by cellular recycling structures known as autophagosomes.

Through cell culture experiments, biochemical and molecular biological studies, as well as computer simulations, Professor Ivan Đikić and his scientific team from Goethe University Frankfurt conducted groundbreaking research. Their investigation focused on the membrane curvature receptor FAM134B, and they successfully demonstrated that ubiquitin plays a pivotal role in promoting and stabilizing the formation of FAM134B protein clusters within the ER membrane. Consequently, ubiquitin drives the process of ER-phagy. Professor Đikić explains the mechanism, stating that ubiquitin enhances the stability of FAM134B clusters and causes the ER to protrude further at these specific locations. The intensified membrane curvature, in turn, leads to additional reinforcement of the clusters and attracts other proteins involved in membrane curvature. Thus, the effect of ubiquitin becomes self-reinforcing. The team also utilized super-high resolution microscopy to observe and detect the formation of these clusters.

Đikić further elaborates, stating, "In order to carry out this function, ubiquitin induces a structural alteration in a specific portion of the FAM134B protein. This exemplifies yet another remarkable aspect of ubiquitin, which undertakes a multitude of tasks to ensure the proper functioning of various cellular processes."

The significance of ER-phagy becomes evident through the manifestation of diseases associated with a defective FAM134B protein. Professor Christian Hübner and his team at Jena University Hospital have previously identified mutations in the FAM134B gene that give rise to an extremely rare hereditary sensory and autonomic neuropathy (HSAN), characterized by the degeneration of sensory nerves. Consequently, affected individuals are unable to accurately perceive pain and temperature, leading to a heightened risk of unnoticed stresses or injuries that can progress into chronic wounds. In a longstanding collaboration between Jena University Hospital and Goethe University Frankfurt, FAM134B was identified as the first receptor for ER-phagy, underscoring its crucial role in cellular processes.

Furthermore, mutations in another membrane curvature protein known as ARL6IP1 result in a related neurodegenerative disorder characterized by sensory impairments alongside muscle stiffness (spasticity) in the lower limbs. Professor Christian Hübner and Professor Ivan Đikić, along with their scientific team, have recently discovered that ARL6IP1 is also a component of the ER-phagy machinery. Moreover, they have identified that ARL6IP1 undergoes ubiquitination during the process of ER-phagy. This finding highlights the involvement of ARL6IP1 in the intricate machinery of ER-phagy, further expanding our understanding of the underlying mechanisms associated with these neurodegenerative disorders.

Christian Hübner provides insight into the consequences of the absence of the ARL6IP1 protein in mice, stating, "In mice lacking the ARL6IP1 protein, we observe an expansion and degeneration of the ER as the cells age. This leads to an accumulation of misfolded proteins or protein aggregates, which cannot be effectively cleared from the cell. Consequently, nerve cells, which have a slower renewal rate compared to other cells in the body, undergo cell death. This process ultimately gives rise to the clinical symptoms observed in affected patients and genetically modified mice."

Hübner further explains their hypothesis based on their findings, stating, "According to our data, we propose that the two membrane curvature receptors, FAM134B and ARL6IP1, form mixed clusters during ER-phagy and rely on each other to regulate the normal size and function of the ER. However, further research is necessary to fully comprehend the role of ER-phagy not only in neurons but also in other cell types."

These findings shed light on the critical role of ER-phagy and the interconnectedness of membrane curvature receptors in maintaining the proper functioning and integrity of the ER, highlighting the potential implications for understanding and treating neurodegenerative disorders and other related conditions.

The research teams' findings represent a significant milestone in the understanding of ER-phagy, leading to a deeper comprehension of how cells regulate their functions and maintain cellular homeostasis, as emphasized by Đikić. This knowledge not only provides captivating insights into the remarkable capabilities of our cells but also holds vital implications for medicine. Understanding the mechanisms of ER-phagy is essential for comprehending various diseases, enabling timely diagnosis, and facilitating the development of novel therapeutic approaches to aid patients. The newfound understanding of cellular homeostasis and its dysregulation in diseases opens up avenues for advancing medical interventions and improving patient outcomes.