Research

31 Aug 2018
  • Research Result

Cell stress is bad for the mind

Kyoto University finds a new mechanism for psychiatric disorders, opening the door for potential future therapy

Kyoto, Japan -- Psychiatric disorders arise from multiple symptoms, making treatment difficult due to a still rudimentary understanding of the core mechanisms underlying the causes.

In two papers from Kyoto University, a research group reports that certain types of psychiatric symptoms arise from neural circuit impairment induced by abnormal autophagy in the brain.

Autophagy is a process where cells disassemble and recycle unnecessary or nonfunctional components, and research has shown that its dysfunction is associated with cancer and some neurodegenerative disease.

In the first study published in Human Molecular Genetics, the team found that disruption of autophagy genes in certain neurons cause noticeable cognitive impairment in mice.

"Ulk2 is a gene essential for activating autophagy," explains Toshifumi Tomoda from the Graduate School of Medicine, who leads the study.

"We found that removing Ulk2 in mice leads to elevated expression of a protein called p62, indicative of decreased autophagy. When we looked at the brains of these mice, we found dysfunction in the prefrontal cortex."

The prefrontal cortex is a key region controlling executive function and attention. The team observed that the neurons in this region had decreased inhibitory receptors, which lead to impaired and abnormal cognitive functions in the experimental mice.

Moreover, by then utilizing an autophagy-inducing agent, the scientists were able to observe improvements in both the expression of the receptor and the mice’s behavior.

The team also report that deregulated autophagy can affect the minds of humans as well. Collaborating with scientists from Johns Hopkins University, the group showed that cultured human olfactory neurons taken from schizophrenic and bipolar disorder patients also have weakened autophagy.

"Our study demonstrates that deregulated autophagy is a relevant pathophysiological mechanism underlying abnormal cognitive functions," continues Tomoda.

"While neuropsychiatric disorders are generally characterized by several types of clinical manifestations, available antipsychotics may not be effective for all those symptoms."

In the second paper published in Science Advances, the group demonstrated another example of linking deregulated autophagy to psychiatric disorders. The team analyzed mice simulating a disorder known as 22q11.2 deletion syndrome, where a small section of chromosome 22 is deleted. This condition has been known to be associated with psychiatric disorders, and more recently, Parkinson’s disease.

Their results showed that p62 protein levels are elevated in various brain regions, including the prefrontal cortex, indicating that deregulated autophagy may serve as a shared underlying mechanism for multiple psychiatric disorders. The team hopes their work will result in new strategies for treating mental illnesses.

"Targeting the p62-associated autophagic signaling cascade may be a future therapeutic target for certain antipsychotic drugs," concludes co-author Takeshi Sakurai. "But since autophagy happens in practically all cells in the body, we must be cautious and study any possible side effects."  (by Xiou Wang)

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Researchers find that abnormal autophagy in neurons can lead to certain types of psychiatric symptoms (Kyoto University/Tomoki Shimizu)

Paper Information1

【DOI】https://doi.org/10.1126/sciadv.aar6637

【KURENAI ACCESSURL】http://hdl.handle.net/2433/234197

Akiko Sumitomo, Kouta Horike, Kazuko Hirai, Nancy Butcher, Erik Boot, Takeshi Sakurai, Frederick C. Nucifora Jr., Anne S. Bassett, Akira Sawa and Toshifumi Tomoda (2018). A mouse model of 22q11.2 deletions: Molecular and behavioral signatures of Parkinson’s disease and schizophrenia. Science Advances, 4(8):eaar6637.

Paper Information2

【DOI】https://doi.org/10.1093/hmg/ddy219

Akiko Sumitomo, Hiroshi Yukitake, Kazuko Hirai, Kouta Horike, Keisho Ueta, Youjin Chung, Eiji Warabi, Toru Yanagawa, Shiho Kitaoka, Tomoyuki Furuyashiki, Shuh Narumiya, Tomoo Hirano, Minae Niwa, Etienne Sibille, Takatoshi Hikida, Takeshi Sakurai, Koko Ishizuka, Akira Sawa, Toshifumi Tomoda (2018). Ulk2 controls cortical excitatory–inhibitory balance via autophagic regulation of p62 and GABAA receptor trafficking in pyramidal neurons. Human Molecular Genetics, 27(18), 3165-3176.