AsianScientist (Aug. 27, 2018) – Researchers in Japan and Canada have identified a genetic defect and a biological pathway that may contribute to both schizophrenia and early-onset Parkinson’s disease. They published their findings in Science Advances.
Parkinson’s disease (PD) is caused by the loss of dopaminergic neurons in the brain, resulting in motor and cognitive decline. It has been estimated that PD affects one percent of all individuals above sixty years of age. Early onset of PD, which occurs when a person is less than fifty years old, is less common, albeit just as debilitating.
In this study, researchers led by Professor Toshifumi Tomoda at the Kyoto University Graduate School of Medicine in Japan, with collaborators at the Centre for Addiction and Mental Health in Canada, sought out the molecular basis of PD. They began by studying chromosome 22q11.2 deletions, which are known to be associated with schizophrenia (SZ).
His team observed elevated levels of α-synuclein and p62 proteins—major constituents of Lewy bodies, a pathological hallmark of PD—in mouse models with 22q11.2 deletions. These mice also exhibited motor coordination and psychiatric deficits, falling off a rotating bar (known as a rotarod test) more quickly than their non-mutant counterparts. Collectively, these results indicate that mouse models with 22q11.2 deletions may be relevant to the study of PD in addition to SZ.
“Studying 22q11.2 deletions may provide a rare but unique opportunity to address common risk pathways that ultimately render susceptibility to both disease categories,” said Tomoda.
The researchers also found that both SZ and PD deficits were decreased when mice bearing 22q11.2 deletions were treated with a rapamycin analog, which inhibits the mTOR pathway. The mTOR pathway is involved in autophagy, a major cellular clearance system that helps cells flush out and replace old proteins and damaged organelles. An impaired autophagy process results in the accumulation of Lewy bodies. What this suggests is SZ and PD have a common root cause, the researchers said.
“The primary objective of our study was to delineate a possible common mechanism shared by SZ and PD,” Tomoda explained. “The mTOR pathway that we tested may be one of those pathways.”
The study authors noted that the manifestation of psychiatric symptoms and motor deficits are complex, but they hope that a better understanding of the pathological mechanisms manifested in the 22q11.2 mouse models will help identify potential therapies for both SZ and PD. Going forward, the team plans to study the brains of humans with 22q11.2 deletions, using post-mortem brain samples deposited in a brain bank repository. The findings in human brains would complement their work in mouse models.
“We believe this ‘bench-to-bedside, back to bench’ approach can facilitate progress in identifying new therapeutic avenues for those suffering from SZ and PD,” said Tomoda.
The article can be found at: Sumimoto et al. (2018) A mouse model of 22q11.2 deletions: Molecular and behavioral signatures of Parkinson’s disease and schizophrenia.
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