Scientists have gained some new insights into the behavior of a protein coded by a gene called progranulin (PGRN), mutations of which have been linked to frontotemporal dementia (FTD); they believe their findings represent an important step in understanding more about FTD, a little-known, non-Alzheimer’s form of dementia, that causes between 2 and 10 per cent of all cases of dementia.
The study is published in the 18 November online issue of Neuron, and is the work of senior author Dr Stephen M. Strittmatter of Yale University School of Medicine and colleagues.
Strittmatter, who is the Vincent Coates Professor of Neurology and director of the Program in Cellular Neuroscience, Neurodegeneration and Repair at Yale, told the media that:
“Dementia threatens to overwhelm our health system, yet there is relatively limited research funding to understand and develop treatments for Alzheimer’s, and even less for other forms of dementia.”
Alzheimer’s disease accounts for around 60 per cent of dementia cases and is characterized by large amounts of amyloid plaques in the brain which is not characteristic of FTD, although in both diseases, patients show memory problems and cognitive decline.
The main feature of FTD is the degeneration of nerve cells primarily in the frontal and temporal lobes of the brain, and the disease tends to progress slightly differently to Alzheimer’s: some patients with FTD develop language problems and some start to behave in socially inappropriate ways.
While there has been some advance in differentiating between Alzheimer’s and other dementias, for instance using PET scans to look for amyloid build-up, there are currently no good treatments for dementia.
Strittmatter said it was important to know more about what happens at the molecular level in the different types of dementia because this could show that each needs a different type of treatment.
There is some evidence that inherited forms of FTD are linked to mutations of the gene progranulin (PGRN), but little is known about how the gene causes dementia. What we do know is that it is involved with wound repair.
With in vitro and in vivo methods, the latter using laboratory mice, Strittmatter and colleagues:
- Established that PGRN protein binds to neurons with high affinity, suggesting there is a “binding partner”.
- Identified the receptor protein Sortilin (also called Sort1) as the high-affinity binding site for PGRN.
- Showed that PGRN is secreted by “microglia”, the main defence mechanisms of the immune system in the brain and central nervous system (it was “most strongly expressed by activated microglial cells after injury”).
- Found that once it is bound to Sortilin, PGRN quickly enters cells and collects in lysosomes (the cellular waste disposal units that recycle cell material and break down bacteria and other unwanted matter captured by the immune system).
- Demonstrated that mice that do not have Sortilin have much higher levels of PGRN (“elevations in brain and serum PGRN levels of 2.5- to 5-fold”).
They concluded that the binding role that Sortilin plays in conducting PGRN into brain cells and their lysosomes is likely to be a vital clue to how FTD develops and progresses.
Strittmatter said these findings were “just a first step of molecular understanding of this dementia”.
“Eventually we hope to find a way to intervene in the disease and prevent or alleviate symptoms of dementia,” he added.
Funds from the National Institutes of Health, the ALS Association, the Falk Medical Research Trust, an anonymous donor and the Canadian Institutes of Health helped pay for the study.
“Sortilin-Mediated Endocytosis Determines Levels of the Frontotemporal Dementia Protein, Progranulin.”
Fenghua Hu, Thihan Padukkavidana, Christian B. Vægter, Owen A. Brady, Yanqiu Zheng, Ian R. Mackenzie, Howard H. Feldman, Anders Nykjaer, Stephen M. Strittmatter.
DOI:10.1016/j.neuron.2010.09.034
Additional sources: Yale News, wikigenes.
Written by: Catharine Paddock, PhD