Restoring autophagy reverses key signs of brain dysfunction

A research group led by Professor Noboru Mizushima and Assistant Professor Tomoya Eguchi of the Graduate School of Medicine at the University of Tokyo, in collaboration with Keio University and Niigata University, demonstrated in mice that neurological dysfunction caused by autophagy deficiency can be restored by its reactivation. This showed the possibility that brain function deteriorated by neurodegenerative diseases can be improved post-onset through the enhancement of intracellular quality. It is expected to contribute to the treatment of various neurodegenerative diseases. The findings were published in the June 25 issue of Science.

Autophagy is a mechanism that recycles nutrients and degrades unnecessary intracellular proteins and other components and is known to be essential for maintaining biological homeostasis. The research group had previously confirmed that genetically modified mice with suppressed brain autophagy developed accumulation of abnormal protein aggregates in neurons and experienced neurological dysfunction. On the other hand, it remained unclear whether neuronal function impaired by autophagy suppression could recover its function once autophagy was restored.

Therefore, the research group developed "Atg101-tTS mice," which allow brain autophagy to be reversibly switched on and off depending on the presence or absence of drug (doxycycline) administration. Atg101 is one of the essential genes for autophagy. In these mice, autophagy is turned off with a normal diet and turned on with a doxycycline-containing diet. In both males and females of these mice, nearly all individuals die after 4 to 6 weeks of autophagy suppression.

In their experiment, using these mice at 13 to 15 weeks of age, they investigated whether neurological symptoms and other parameters changed by suppressing autophagy for 4 weeks and subsequently restoring it. As a result, after 4 weeks of suppression, p62 (a protein degraded by autophagy) aggregates, which had not been previously observed, were detected throughout the brain. Motor abilities, as well as memory and learning capacities, also declined.

Next, when allowed to recover for 4 weeks following suppression, the disappearance of these aggregates was confirmed. Motor functions such as balance and gait recovered, and the restoration of memory and learning capacities was also confirmed. Furthermore, they verified that axonal swellings, as well as reductions in the number and size of synapses caused by autophagy suppression, improved with the recovery of autophagy. Intracellular protein expression levels were also confirmed to increase during suppression and decrease during recovery. It is believed that as long as neuronal cell death has not occurred, symptom improvement can be expected through the recovery of autophagy.

Mizushima stated, "These results were quite unexpected even for us, as they demonstrated that brain function can be restored by reactivating autophagy. Most neurodegenerative diseases characterized by the accumulation of abnormal proteins, such as Parkinson's disease, amyotrophic lateral sclerosis (ALS), and tau-related disorders, with the exception of hereditary cases, are conditions that are noticed only after symptoms appear. However, we believe this study shows that even after symptoms have already emerged, improving intracellular quality holds the potential to ameliorate those symptoms."

Journal Information
Publication: Science
Title: Reversible suppression of autophagy in a mouse model reveals neuronal resilience
DOI: 10.1126/science.ady3911