Many cells in our body, such as those which make up our brain, need to last a lifetime. Our cells have developed ways of protecting themselves from damage that can occur throughout life and during disease.
This includes a process called ‘autophagy’, which means “self-eating”. Autophagy is the major route by which harmful and damaged components are collected together and destroyed within our cells. Such breakdown of cellular material is also an important recycling process that generates new building blocks to keep our cells and tissues healthy.
In a new study published this week in the New England Journal of Medicine, the researchers identified a unique group of patients with mutations in a key gene essential for autophagy, which causes a very specific neurological disease.
The study was led by Professor Rob Taylor at Newcastle University and involved multiple international laboratories, including researchers at the University of Helsinki.
The study showed that in exceptional circumstances, patients can survive to adulthood despite defective autophagy. A total of five patient families were discovered in the UK, France, Switzerland, Germany and Saudi Arabia.
Detailed molecular analysis of patient cells revealed that the mutations impaired the function of ATG7, a core protein that controls autophagy. This was followed up with further mechanistic studies in human, mouse and yeast cells, confirming a severe defect in autophagy. Because inactivation of ATG7 leads to neonatal death in mice, it was thought such human patients could likely never exist.
Critical collaboration with the University of Helsinki
Tom McWilliams is a neuroscientist and a senior co-author on the study, whose laboratory focuses on the role of autophagy and metabolism during tissue development and degeneration. His laboratory contributed expertise and data for the molecular profiling of the patient cells. Commenting on the study, McWilliams said:
“This discovery was a real surprise and cements the clinical importance of autophagy for neurodegenerative disease. We have known for a long time that autophagy is very important in the mouse nervous system. To unearth these human consequences represents a critical step forward towards defeating degeneration. Furthermore, it underscores the vital necessity of discovery science for future breakthroughs in disease research.”
Jack Collier is a lead author on the study, who recently successfully defended his PhD from the Taylor lab at Newcastle University and is now a postdoc at McGill University. Collier spent time in Helsinki as a prestigious EMBO fellow in the McWilliams lab.
Postdoctoral fellow Fumi Suomi was able to conduct critical experiments using patient cells that authenticated impaired autophagy activity. The researchers intend to continue their collaboration to obtain further unique insights into the role of autophagy in human health and disease.
Developmental Consequences of Defective ATG7-mediated Autophagy in Humans. Collier JJ, Guissart C, Olahova M, Sasorith S, Piron-Prunier F, Suomi F, Zhang D, Martinez-Lopez N, Leboucq N, Bahr A, Azzarello-Burri S, Reich S, Schols L, Polvikoski TM, Meyer P, Larrieu L, Schaefer AM, Alsaif HS, Alyamani S, Zuchner S, Barbosa IA, Deshpande C, Pyle A, Rauch A,Synofzik M, Alkuraya FS, Rivier F, Ryten M, McFarland R, Delahodde A, McWilliams TG, Koenig M, Taylor RW (2021). New England Journal of Medicine. DOI: 10.1056/NEJMoa1915722