AsianScientist (Apr. 24, 2019) – Scientists in Japan have discovered that when a normal cellular cleanup process is disrupted, mice start behaving in ways that resemble human symptoms of autism spectrum disorder (ASD) and schizophrenia. Their findings are published in the journal Science Advances.
Like city streets with no garbage collection, cells can get choked if a process known as autophagy—‘auto’ for ‘self’ and ‘phagy’ which means ‘to eat’ in ancient Greek—does not work properly. Autophagy has been implicated in a host of diseases, including cancer and neurological diseases.
In this study, researchers led by Professor Motomasa Tanaka at the RIKEN Center for Brain Science, Japan, sought to understand the impact of impaired autophagy on the functioning of neurons. They found that loss of normal autophagy influenced how brain cells react to inhibitory signals from each other, and contributes to behavioral changes in mice.
For autophagy to begin, cells need to contain a protein encoded by the gene Atg7. The researchers made knockout mice by selectively deleting this gene from two cell populations—excitatory and inhibitory interneurons—which are known to be the malfunctioning culprits in many neurodevelopmental and neuropsychiatric disorders. The mice in both groups displayed overlapping behavioral abnormalities such as increased anxiety and reduced social interaction and nesting behavior.
“The loss of autophagy in different types of neurons had the same behavioral effects, which hinted that a common mechanism was at work,” said Tanaka.
Picking through the cellular ‘trash’ that accumulated in the affected cells, the researchers identified aggregates of proteins made up of GABARAPs, a group of proteins that help bring receptors for the main inhibitory neurotransmitter GABA to the cell surface. Not only had these proteins accumulated, they were being dumped into aggregates containing another protein called p62.
“Think of autophagy as the recycling depot and p62 as the garbage trucks that go around the cell to pick up trash labeled for recycling,” said Dr. Kelvin Hui of RIKEN. “When the recycling depot experiences a shutdown or reduced capacity, p62 has nowhere to bring this garbage and it starts to pile up in the cell, leading to major problems.”
Due to the trapped GABARAPs, the GABA receptors were not transported to the neurons’ cell surface, causing the neurons to become hyperactive. The research team also looked at post-mortem human brain samples from a subset of patients with ASD and observed the same protein aggregation and increase of p62. This finding, together with previous research on genetic deletions in patients with ASD and intellectual disability, further implicates disrupted autophagy and protein aggregation in the pathogenesis of these conditions.
The research team thus believes that small molecules that restore autophagy or disrupt the formation of harmful protein aggregates could be useful in the treatment of neurodevelopmental and neuropsychiatric disorders.
The article can be found at: Hui et al. (2019) GABARAPs Dysfunction by Autophagy Deficiency in Adolescent Brain Impairs GABAA Receptor Trafficking and Social Behavior.
Source: RIKEN; Photo: Shutterstock.
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