Christine Van Broeckhoven
talks with ScienceWatch.com and answers a few
questions about this month's New Hot
Paper* in the field of
Neuroscience & Behavior.
Article Title: Null mutations in progranulin cause
ubiquitin-positive frontotemporal dementia linked to
Authors: Cruts, M, et el.
Year: AUG 24 2006
* Univ Antwerp VIB, Dept Mol Genet, Neurodegenerat Brain
Dis Grp, Univ Pl 1, BE-2610 Antwerp, Belgium.
* Univ Antwerp VIB, Dept Mol Genet, Neurodegenerat Brain
Dis Grp, BE-2610 Antwerp, Belgium.
* Inst Born Bunge, Neurogenet Lab, BE-2610 Antwerp,
(addresses have been truncated)
Why do you think your paper is
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,
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.
"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
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, , 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
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
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
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
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
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
* 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.