A study published in the American Journal of Human Genetics By researchers at Baylor College of Medicine and the Jan Duncan Neurological Research Institute (Duncan Nri) at the Texas Children’s Hospital provides solutions to the pressing need to identify factors that influence the risk or resistance of Alzheimer’s disease (AD) while providing a way to explore possible biological markers and therapeutic objectives.
The researchers integrated computational and functional approaches that allowed them to identify not only specific genes whose alterations predicted a higher risk of AD in humans and behavioral impediments in the fruit flies of the fruit AD, but also showed that reverting the changes in the gene has a neuroprotective effect on living organisms.
“Alzheimer’s disease affects more than 50 million people worldwide and, although researchers have learned a lot about the years, their causes are not yet completely understood and effective therapies are not yet available,” said the corresponding author, Dr. Juan Boots, professor of molecular and human genetics and Baylor’s molecular and cellular biology. Boots is also the director of the High Performance Behavior Detection Nucleus in Duncan NRI.
Although the extensive studies of the entire genome have discovered hundreds of genes potentially associated with the disease, it is necessary to evaluate the roles that these genes play in the EA to distinguish those that confer the risk of the condition of the not involved spectators.
“We address this problem by first integrating the published data of the association of the entire genome with multiple computational approaches to identify genes probably involved in AD,” said the co-first author Morgan C. Stephens, a student graduated in the boots laboratory. “Then we tried those computational predictions experimentally in the laboratory.”
The researchers systematically disturbed the candidate genes of AD identified from their computer analysis and evaluated their potential to modulate neuronal dysfunction and cell alterations related to AD, such as neuropathology or the accumulation of Tau proteins, in living organisms.
“We work with fruit fly models of the condition to assess whether these altered genes promoted the neuronal dysfunction that leads to motor impediments. It is important to highlight that we also investigate whether to revert the activity of those altered genes would also reverse the motor alterations in flies and tau or accumulation of bet-amyloid proteins in the cells,” said boots.
Computational analyzes revealed 123 candidates for the risk of AD and the team confirmed that the expression of many of them is altered in the human AD and correlates with the accumulation of Tau or beta-amyloid protein in brain cells affected by the condition. The evaluation of 60 of these genetic candidates available in fruit fly models pointed to 46 that modulated neuronal dysfunction in one or both fly models. The altered expression of 18 of these genes predicted the increased risk of ad in humans.
It is important to highlight that reverting the alterations in 11 of these genes protected the flies of the fruit of damage to their nervous system.
“In the list of final candidates, MTCH2 He appeared to be at the top of functional studies, “Stephens said.”MTCH2 The expression is negatively regulated in human ado brain samples, and the reduction of its function in flies aggravates motor dysfunction. It was very exciting to discover what to restore MTCH2 Expression in inverted flies Motor dysfunction and reduction of the accumulation of Tau in human neural progenitor cells in the laboratory. “
“Our findings support a greater exploration of MTCH2 For therapeutic purposes and highlight the value of a combined computational and experimental approach to discover main genetic players in Alzheimer’s disease and other neurodegenerative conditions, “Boots said.
Other taxpayers to this work include the co-first author Jiayang Li, as well as Megan Mair, Justin Moore, Katy Zhu, Akash Tarkunde, Bismark Amoh, Alma M. Pérez, Arya Bhakare, Fangfei Guo, Joshua M. Shulman and Ismael Al-Ramahi. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, the Jan and Duncan Neurological Research Institute in the Texas Children’s Hospital and the center of Alzheimer’s and Neurodegenerative disease of Alzheimer’s neurodegenerative disease.
This work was supported by NIH subsidies U01AG072439, R01AG074009 and F31NS129062.