NEW HOT PAPERS

Why do you think your paper is highly cited?

The paper contributed significantly to our understanding of the genetic etiology of frontotemporal lobar degeneration (FTLD). FTLD is, after Alzheimer disease, the second most common dementia subtype among the 50 to 60 years-old age group.

This paper describes the genetic search for the underlying gene defect in autosomal-dominant FTLD families that were previously linked to a chromosomal region at 17q21. In the same chromosomal region lies the gene encoding for the microtubule associated protein tau (MAPT), which is the first gene that was identified for FTLD (Hutton M., et al., “Association of missense and 5’-splice-site mutations in tau with the inherited dementia FTDP-17,” Nature, 393: 702-705, 1998.).

In contrast to MAPT mutation carriers, no tauopathy, i.e., protein aggregates that are immunostaining for tau, is present in autopsied brains of progranulin (PGRN) mutation carriers. They were classified as FTLD-U, indicating a tau-negative, but ubiquitin-positive pathology.

To date, we know that TDP-43 is a major component of these FTLD-U aggregates (Neumann M et al., “Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis,” Science 314, [5796], 130-133, 2006).

Does it describe a new discovery, methodology, or synthesis of knowledge?

It shows that the mutation mechanism by which progranulin contributes to the disease process in FTLD is haploinsufficiency, with a wide spectrum of loss-of-function mutations at both the mRNA and protein levels. This finding also provides a direct link between loss of growth factor progranulin and the CNS neurodegeneration process in FTLD patients.

Progranulin is a secreted growth factor, and its mechanism of action in the neurodegeneration process is now being profoundly investigated. One can expect that progranulin will open new avenues for treating FTLD patients.

Would you summarize the significance of your paper in layman’s terms?

Frontal temporal lobar dementia (FTLD) is a common subtype of dementia affecting a large number of individuals, particularly among the younger age group of 50- to 60-year-olds. FTLD is a devastating disease that profoundly affects different aspects of a person’s being, taking away one’s dignity and disrupting an individual’s entire family dynamic.

There is not yet a cure for FTLD that stops or slows the disease process. The identification of a link between loss of the growth factor progranulin and loss of neurons in FTLD opens new avenues for studying the mechanisms that lead to dementia. Also, in the long run, it might provide novel opportunities for developing new ways for an effective treatment of these patients.

How did you become involved in this research, and were there any particular problems encountered along the way?

As a molecular geneticist, I have been searching for the disease genes underlying neurodegenerative diseases of the central end peripheral nervous system for nearly 25 years. Looking back, it is clear to me that each time a successful identification of a disease gene is made it has opened a wealth of research by many neuroscientists, leading to some very important findings which are currently being pursued in several therapeutic approaches to some of the most devastating diseases among humans.

One such prototype example is Alzheimer’s disease (AD), for which the identification of a direct genetic link between AD and mutations in the amyloid precursor protein gene (APP) was instrumental to the current concept of anti-amyloid therapeutics.

We identified the FTLD families segregating PGRN mutations in Belgium and the Netherlands, showing those that were linked to chromosome 21q21 but did not carry MAPT mutations. Since the patients in these families did not have a tauopathy, we assumed that there might be another gene involved. However, the presence of MAPT made us insecure and we spent considerable time on excluding any possible involvement of MAPT. Looking back, this actually delayed the identification of progranulin by nearly three years.

Where do you see your research leading in the future?

We have made a major investment in functional studies of progranulin, both in cellular and mice models, which should help us understand more about the role of this growth factor in normal and disease processes taking place within the human brain. We hope to contribute to the development of an effective treatment for FTLD.

Are there any social or political implications for your research?

The finding that progranulin is a major genetic contributor to an increased risk for FTLD, has led to the inclusion of this gene in DNA diagnostic testing of patients and their relatives. In Belgium, these tests are performed in government-subsidized medical genetic centers, following strict medical and ethical guidelines.

Christine Van Broeckhoven, Ph.D., D.Sc.
Professor of Molecular Biology and Genetics
& Science Director
Department of Molecular Genetics
Flanders Institute for Biotechnology (VIB)
University of Antwerp
Antwerpen, Belgium

* Note, this comment (received March 2008) pertains to a previous data period. View the list of New Hot Papers for source date information regarding that period.