Uncovering the Roots of Neurodegenerative Disorders Through Cell Self-Digestion

Scientists from Frankfurt and Jena have decoded how the impaired recycling process of the endoplasmic reticulum can lead to neurodegenerative conditions. Image Credit: Manja Schiefer for Jena University Hospital.

Scientists have figured out the regulatory mechanisms that control the form and function of the endoplasmic reticulum (ER).

The ER is an intricate network of channels, sacs, and compartments encased in membranes present throughout the cells of humans, animals, plants, and fungi. It operates as a protein factory, managing their synthesis, ensuring they fold into the correct 3D shape, and modifying them as required. Moreover, the ER plays an essential role in lipid and hormone production and is critical in preserving the cell’s calcium equilibrium.

The ER also provides the base for the cell’s transportation system, aiding the movement of substances within the cellular setting. It further contributes to quality control by directing wrongly folded proteins towards the cell’s internal waste disposal mechanism. Plus, it neutralizes detrimental toxins that infiltrate the cell, thereby protecting the cell’s functionality and well-being.

Given its myriad roles, the ER is continuously reshaped. A mechanism named ER-phagy (approximately “self-digestion of the ER”) governs the degradation of the ER. Involved are a group of signal-receiving proteins or receptors that manage the membrane curvatures of the ER, hence shaping its various forms in the cell.

During ER-phagy, these receptors gather at particular locations on the ER and augment membrane curvature to the point where part of the ER is constricted and disintegrated into its constituent parts by cellular recycling entities (autophagosomes).

Through a superior-resolution microscopy technique, scientists observed how FAM134B proteins cluster after triggering ER-phagy in the endoplasmic reticulum. Image Credit: Gonzáles et al., Nature (2023).

In cell culture experiments, biochemical and molecular biology studies, and computer simulations, the research team headed by Professor Ivan Đikić of Goethe University Frankfurt initially examined the membrane curvature receptor FAM134B, showing that ubiquitin aids and solidifies the formation of FAM134B protein clusters in the ER membrane.

Ubiquitin, in turn, propels ER-phagy. Đikić notes: “Ubiquitin makes FAM134B clusters more stable and causes more prominent bulges in the ER at these locations. This increased membrane curvature further stabilizes the clusters and draws additional membrane curvature proteins, reinforcing ubiquitin’s effect.” The researchers could also spot cluster formation using high-resolution microscopy.

Đikić adds: “Ubiquitin alters the shape of a portion of the FAM134B protein to accomplish this function, representing another aspect of ubiquitin’s remarkable versatility in maintaining diverse cellular functions.”

The significance of ER-phagy is demonstrated by disorders arising from a defective FAM134B protein. A team led by Professor Christian Hübner from Jena University Hospital previously found mutations in the FAM134B gene causing a rare hereditary sensory and autonomic neuropathy (HSAN), where sensory nerves perish, making patients incapable of accurately sensing pain and temperature. This can lead to unnoticed stresses or injuries that can evolve 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.

Mutations in another membrane curvature protein, ARL6IP1, lead to a comparable neurodegenerative disorder that merges sensory defects with muscle stiffening (spasticity) in the legs. The scientific team led by Christian Hübner and Ivan Đikić has now found that ARL6IP1 is also part of the ER-phagy machinery and is ubiquitinated during ER-phagy.

Christian Hübner explains: “In mice lacking the ARL6IP1 protein, we observe that the ER virtually expands and deteriorates as cells age, leading to an accumulation of misfolded proteins or protein aggregates that are no longer disposed of in the cell. As a result, nerve cells, which don’t renew as quickly as other body cells, die, causing clinical symptoms in affected patients and genetically modified mice. We deduce from our data that the two membrane curvature receptors, FAM134B and ARL6IP1, form mixed clusters during ER-phagy and rely on each other to maintain the normal size and function of the ER. Further research will be necessary to completely understand the role of ER-phagy in neurons as well as in other cell types.”

However, the research groups have taken a significant step toward comprehending ER-phagy, Đikić believes: “We now have a better understanding of how cells regulate their functions, leading to what we call cellular homeostasis. This knowledge provides amazing insights into the extraordinary capabilities of our cells in biology, and it is vital for understanding diseases, timely diagnosis, and the development of new therapies in medicine.”

References: “Ubiquitination regulates ER-phagy and remodeling of endoplasmic reticulum” by Alexis González et al., 24 May 2023, Nature.
DOI: 10.1038/s41586-023-06089-2

“Heteromeric clusters of ubiquitinated ER-shaping proteins drive ER-phagy” by Hector Foronda et al., 24 May 2023, Nature.
DOI: 10.1038/s41586-023-06090-9

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