Fruit Fly Study Probes Protein Role in Aggressive Dementia
New mechanisms have been uncovered in the development of an aggressive form of dementia called frontotemporal dementia. This is the third most common form of early-onset dementia, often beginning in the patient’s 50s.
“Frontotemporal” refers to the two lobes of the brain that become damaged in this type of dementia. The frontal lobes of the brain, behind the forehead, control behavior, emotions, and language. The temporal lobes, on either side of the brain, control our understanding of words.
Frontotemporal dementia is caused when nerve cells in one or any of these lobes of the brain die, and changes occur in their connecting pathways. Brain tissue in the frontal and temporal lobes shrinks over time.
This causes language abilities to be affected, and personality and behavior change, so the patient may be become excessively uninhibited in social situations.
In contrast with Alzheimer’s disease, individuals with early-stage frontotemporal dementia tend not to have problems with day-to-day memory or with visual skills such as judging distances between objects.
A team led by Dr. Sean Sweeney of York University, U.K., collaborated with researchersÂ at the University of Massachusetts Medical School and University of Puerto Rico. Together, they looked at how the connections between synapses can be affected by changes in a protein named CHMP2B, a subunit of cell machinery called endosomal sorting complexes required for transport (ESCRT).
In lab tests on the effects of CHMP2B on Drosophila, a species of fruit fly, they discovered mechanisms that caused synapses to overgrow.
The signals involved were previously known to affect immune reactions, but have not before been seen to impact synapse growth. Altered endosome function was also seen. This means that material within cells is not broken down correctly.
“These findings shed light on the events occurring in neurons as dementia takes hold,” said Dr. Sweeney. “The more we know about the steps that occur in disease progression, the more opportunities we have to intervene with potential therapies.”
The research was published in The Journal of Cell Biology. This data points to defective endosome function as creating defective “synaptic growth regulation during neurodegenerative processes,” they report.
Co-author Dr. Ryan West said, “We hope that this work helps to tease apart complex molecular processes occurring in neurons and identify how these can go wrong in neurodegenerative diseases, such as frontotemporal dementia.”
The team hopes the novel steps in disease progression identified here could be targeted by drugs to halt cognitive decline.
Commenting on the work, Dr. Clare Walton of the Alzheimer’s Society said, “We know less about the underlying causes of frontotemporal dementia than some other kinds of dementia so research like this is a vital step towards developing treatments for the condition. Further research will be needed to determine whether this mechanism plays a similar role in humans.”
In an editorial about the study, Dr. Ben Short of Rockefeller University, New York, N.Y., states that synaptic growth is stimulated by defects in endosomal function, resulting in neurodegeneration.
“Mutations in the gene encoding the ESCRT-III subunit CHMP2B have been linked to frontotemporal dementia,” he writes. “Additionally, a protein called POSH accumulates on endosomes. Removing POSH from Drosophila flies restored synaptic growth to normal levels.”
The findings were confirmed in studies on mammals, where POSH accumulation in neurons led to synaptic overgrowth. “The same pathways could also promote neurodegeneration,” he concludes.
A further protein which may influence the development of frontotemporal dementia was also identified. Called RAB8, it plays a role in regulating the movement of material along cell membranes.
Fruit flies lacking the RAB8 protein were used to explore the role of RAB8 deficiency. As predicted, it led to an overgrowth of the connections between neurons. Hence, it is now thought that RAB8 is involved in regulating the growth of neurons which are damaged in frontotemporal dementia, and that treatment to increase RAB8 may slow this type of neurodegeneration.
Sweeney now aims to identify additional genes involved in the process, again using their fruit fly models of frontotemporal dementia.
Genes are believed to be very important in frontotemporal dementia as it runs in families more often than other forms of dementia.
About one-third of patients have some family history of dementia, and about 10 percent to 15 percent have a strong family history of it, with several close relatives in different generations affected.
The children or siblings of someone with one of the mutations known to cause frontotemporal dementia have a 50 percent risk of carrying the same defective gene and may benefit from a specialist gene testing service.
Ryan, J.H. et al. Rab8, POSH, and TAK1 regulate synaptic growth in a Drosophila model of frontotemporal dementia. Journal of Cell Biology, 23 March 2015 doi: 10.1083/jcb.201404066
Collingwood, J. (2018). Fruit Fly Study Probes Protein Role in Aggressive Dementia. Psych Central. Retrieved on August 11, 2020, from https://psychcentral.com/news/2015/04/27/fruit-fly-study-probes-protein-role-in-aggressive-dementia/83949.html