A team of scientists at the VIB research institute and KU Leuven in Belgium has discovered that an amyloid-beta precursor protein, APP, modulates neuronal signal transmission by binding to a specific receptor called GABABR1a. This has implications for treating Alzheimer’s disease and probably other disorders.
Alzheimer’s-affected brains are clogged with amyloid-beta plaques. These fragments are produced from a precursor protein whose normal function has remained unclear for decades.
In an article in Science on 11 January 2019, a team led by Professors Joris de Wit and Bart De Strooper found that APP signalling suppressed neuronal communication at the synapse. “The newly identified role of the amyloid precursor protein may underlie the neuronal network abnormalities we see in mouse models of Alzheimer’s disease and preceding clinical onset in human patients. It is exciting to consider that a therapy targeting this receptor might attenuate these abnormalities in people with Alzheimer’s,” said Prof De Strooper.
Prof De Wit added that the clinical implications may reach much further than just Alzheimer’s. “Interestingly, GABABR signalling has been implicated in a diverse range of neurological and psychiatric disorders, including epilepsy, depression, addiction and schizophrenia. Now that we know how the secreted part of the amyloid precursor protein modulates neuronal signalling through the GABAB receptor, we could think of new ways to develop drugs that can restore this type of neuronal signalling in other clinical contexts.”
Since the 1980s, several different research teams have traced the protein fragment found in amyloid plaques back to a gene located on chromosome 21. The gene encodes a longer protein that is cleaved into several fragments, one of which ends up in amyloid plaques. Research on Alzheimer’s disease tended to focus on the cleavage process that leads to the formation of the amyloid-beta fragment.
New insights into cancer drug resistance
Scientists at the University of Cambridge, UK have identified mechanisms by which mutations in the ATM gene can lead to cancer drug resistance and how this can be counteracted by changes in other genes. The findings, reported on 8 January 2019 in Nature Communications, show how cells respond to DNA damage as well as highlight potential therapeutic targets for the genetic disease, ataxia-telangiectasia (A-T).
Mutations in the ATM gene cause the rare neurodegenerative disease A-T leading to severe disability. They are also associated with sporadic cancers. Previous research has shown that the ATM protein, which is produced from the ATM gene, protects the genome by spotting DNA damage and promoting its repair. Patients with A-T and ATM-deficient cells however are hyper-sensitive to DNA-damaging agents used in cancer therapy such as PARP inhibitors.
In the paper, Professor Steve Jackson at The Gurdon Institute and colleagues at AstraZeneca Plc describe how the drug sensitivities of ATM-deficient cells can be mitigated by changes in other genes. Using gene editing technology, the authors show that defects in the products of several genes also involved in DNA repair pathways can alleviate the hypersensitivity of ATM-deficient cells to PARP inhibitors and the chemotherapeutic drug topotecan.
“This study marks a major step forward in our understanding of how the ATM protein maintains genome stability and how ATM defects can cause cancer and neurodegeneration in human patients with A-T,” said Prof Jackson.