From the Special Topic of
In the Special Topics analysis on autophagy, the paper
"Inhibition of mTOR induces autophagy and reduces toxicity
of polyglutamine expansions in fly and mouse models of
Huntington disease," (Ravikumar B, et al., Nat.
Genet. 36: 585-95, June 2004) appears on both the
list of the 20 most-cited papers in the past decade and the
Front Map on Autophagy. According to
Essential Science IndicatorsSMfrom
Reuters, this paper has been cited 335 times from its
publication in 2004 to February 28, 2009.
The leading scientist behind this paper is Professor David Rubinsztein,
whose record in the database includes 118 papers, the bulk of which are
classified under Molecular Biology & Genetics, cited a total of 4,402
times. Prof. Rubinsztein is currently Professor of Molecular Neurogenetics
and Wellcome Trust Senior Fellow in Clinical Science in the Department of
Medical Genetics at the University of Cambridge's Cambridge Institute for
In the interview below,
ScienceWatch.com talks with Prof. Rubinsztein about
this paper and its impact on the field of
Would you please describe the significance of
your paper and why it is highly cited?
Many neurodegenerative diseases, including Huntington's disease, are caused
by intraneuronal aggregate-prone proteins. These proteins generally cause
disease by gain-of-function mechanisms, thereby acting as "toxins."
Previously, we had shown in cell culture that such aggregate-prone proteins
could be cleared from the cytoplasm by autophagy. (Ravikumar B, et
al., Hum. Mol. Genet. 11:1107-17, 1 May 2002). Autophagy
is a process whereby cells form double-layered vesicles that engulf a
portion of cytoplasm and deliver these to lysosomes for degradation of
"...we need to try to understand how
autophagy may be involved in a range of
diseases and normal physiological
"I am keen to develop and test
the strategy of inducing autophagy as a
therapy for a range of neurodegenerative
In this Nature Genetics study, we showed that autophagy induction
with rapamycin enhanced the removal of a form of mutant huntingtin (which
causes Huntington's disease), and thereby reduced its toxicity in
transgenic Drosophila and mouse models of Huntington's disease.
I think that this study showed proof-of-principle in vivo for the
possibility that autophagy upregulation may be a therapeutic strategy for
Huntington's disease and related conditions.
The study also shows that once the large aggregates form, they sequester
and inactivate the mammalian target of rapamycin protein (mTOR). mTOR
inactivation is one of the pathways that induces autophagy, and thus this
suggested a possible protective consequence of the large aggregates.
How did you become involved in this research, and
were there any particular successes or obstacles that stand
I had been working on Huntington's disease since 1993 and thought that
reducing the levels of the toxic protein was a possible strategy that one
could consider. One way of doing this was by enhancing its degradation.
While people were very focused on the ubiquitin-proteasome system in the
context of Huntington's disease and related conditions, I became more aware
of autophagy as a process and around 2000 thought that we should test it as
a clearance pathway for Huntington's disease.
Where do you see your research and the broader
field leading in the future?
I am keen to develop and test the strategy of inducing autophagy as a
therapy for a range of neurodegenerative diseases. In conditions like
Huntington's disease, one can identify people at risk who carry the
mutation, as it is inherited in an autosomal dominant manner and most cases
will have a family history. In such cases, there is also the possibility of
starting treatment in asymptomatic mutation-positive cases long before
disease onset, with the aim of delaying the onset of symptoms. This may
require treatment of healthy people for many years. I would like to
identify the safest possible ways of inducing autophagy for these purposes.
This will require a better understanding of the signaling pathways
regulating autophagy, as well as identification of the possible druggable
targets in the autophagy machinery.
What are the implications of your work for this
We have helped to develop the idea that autophagy may be a protective
process in certain conditions, and that its upregulation may be beneficial.
I think that this supports the idea that we need to try to understand how
autophagy may be involved in a range of diseases and normal physiological
processes, and there has certainly been impressive progress from many labs
in these areas in recent years.
Professor David C. Rubinsztein
Department of Medical Genetics
Cambridge Institute for Medical Research
University of Cambridge
Ravikumar B, et al., "Inhibition of mTOR induces
autophagy and reduces toxicity of polyglutamine expansions
in fly and mouse models of Huntington disease," Nat.
Genet. 36(6): 585-95, June 2004. Source:
Essential Science Indicators from
View a Emerging Research Front comment from David C.
Rubinsztein (Dec. 2008).