The cells of higher organisms such as mammals, flies and fungi enclose their genetic material in a nucleus. A nuclear envelope, consisting of two stacked membranes, protects it. For the cell to survive, the nucleus must constantly exchange molecules with the rest of the cell. This exchange relies on channels called nuclear pores, which act as selective gates that transport proteins or messenger RNA in or out. Before this pore complex can be assembled, the cell must first punch an opening through both membranes and then seamlessly seal the edges. How cells accomplish this was a long-standing puzzle.
Now, research teams at the Institute of Biochemistry, led by ETH professors Ulrike Kutay, Karsten Weis and Madhav Jagannathan, together with colleagues from the University of Fribourg and other partners, have solved the puzzle. Their findings not only answer a fundamental question in cell biology but also offer an explanation and a potential therapeutic approach for a hereditary form of dystonia, a rare but severe movement disorder. The corresponding studies have been published in the journal Molecular Cell.
The researchers have shown for the first time that two tools are required for the envelope's two membranes to fuse perfectly: the enzyme Torsin-1A and a complex of several CLCC1 units (in humans) or their fungal counterparts, Brl1 and Brr6. Until now, it was known that a defect in Torsin-1A halts nuclear pore assembly – with fatal consequences for the cell.
The researchers have now shown how this cooperation works: Torsin-1A binds to CLCC1 and helps several of these building blocks join together. Torsin-1A then accompanies the CLCC1 complex to the site of pore assembly to enable membrane fusion.
The exact mechanism of the fusion also caught the research teams by surprise. Using computer simulations, they hypothesised that CLCC1 proteins (or their relatives Brl1 and Brr6 in fungi) forge a temporary channel inside the nuclear envelope. This allows fat molecules (lipids) to flow across the bilayers, rendering the local membrane unstable and forcing the fusion of the two nuclear membranes. “We had not expected such a mechanism,” explains the first author of one of the studies, Daria Maslennikova, who completed her doctorate in Kutay’s group.
These findings shed new light on primary dystonia (DYT1 dystonia), a rare, currently incurable neurological movement disorder. Worldwide, about six in 100,000 people are affected. The disease usually begins in childhood and presents with painful muscle spasms and abnormal postures. To date, the symptoms have been alleviated only through physiotherapy or botulinum toxin injections.
In humans with primary dystonia, a mutation in the Torsin1A gene prevents the Torsin1A molecule from functioning correctly, leaving the CLCC1 complex with insufficient support. Using fruit fly (Drosophila) experiments, the researchers showed that artificially increasing CLCC1 levels can correct defects that occur, for example, during germline cell development.
Why an alteration in the Torsin-1A gene causes symptoms in only about a third of mutation carriers is still unclear, but the researchers speculate that person-specific differences in CLCC1 protein levels may contribute.
“This finding helps us envision a possible therapy,” explains ETH professor Ulrike Kutay. One potential treatment strategy could be to boost CLCC1 production or prevent the protein from breaking down. This approach has already shown success in human cell cultures and in fruit flies. Whether these findings can be successfully translated to humans must first be evaluated in further clinical studies and drug screens.
The scientific breakthrough resulted from close collaboration among research groups at ETH Zurich, the University of Fribourg, the Paul Scherrer Institute (PSI), the European Molecular Biology Laboratory (EMBL) and RWTH Aachen University. The fact that fundamental cellular discoveries can lead to new therapies highlights the enduring value of basic research.
In the future, the teams plan to investigate additional relatives of the enzyme Torsin1A. Human cells also contain other torsins whose precise functions remain unknown. Kutay, Weis, Jagannathan and their colleagues, working in collaboration with plant scientists, aim to determine whether similar molecules and mechanisms also operate in plants.
Molecular Cell
The dystonia-associated Torsin1A sustains CLCC1 function in membrane fusion of the nuclear envelope for NPC biogenesis