David C. Rubinsztein talks
with ScienceWatch.com and answers a few questions
about this month's Emerging Research Front Paper in the
field of Pharmacology & Toxicology.
Article: The roles of intracellular
protein-degradation pathways in
Journal: NATURE, 443 (7113): 780-786 OCT 19 2006
Addresses: Addenbrookes Hosp, Cambridge Inst Med Res, Dept
Med Genet, Hills Rd, Cambridge CB2 2XY, England.
Addenbrookes Hosp, Cambridge Inst Med Res, Dept Med Genet,
Cambridge CB2 2XY, England.
Why do you think your paper is highly
The aim of the paper was to review the current understanding of the
importance of protein degradation pathways in neurodegenerative diseases.
This has been a rapidly evolving field and the paper provided the
opportunity to include a fairly detailed assessment of more recent data
implicating autophagy as an important route for the clearance of
aggregate-prone proteins that cause many neurodegenerative diseases.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
"I have been working on Huntington's
disease and related conditions for about 16
This was a review which aimed to synthesize and appraise our understanding
of the area.
Would you summarize the significance of your paper in
Many neurodegenerative diseases, like
Parkinson's disease and Huntington's disease, are
characterized by the accumulation of specific proteins inside nerve
cells in aggregates. Indeed, the relevant proteins show an enhanced
propensity to aggregate. Furthermore, many of the aggregate-prone
proteins that cause these diseases mediate pathology by a gain-function
mechanism—they act as "toxins" to the cells.
While much of the earlier literature was concerned with the factors that
influence aggregation specifically, this review considered the importance
of pathways that regulate the levels of these "toxins" by influencing their
degradation rates—the toxicity of these proteins and the numbers of
aggregates that form, correlate with degradation rates. There are now many
studies that suggest that impairing the degradation pathways may predispose
to neurodegenerative disease, while upregulating specific pathways may be
How did you become involved in this research and were
any particular problems encountered along the way?
I have been working on Huntington's disease and related conditions for
about 16 years. In 2002, we were the first lab to show that one could
enhance the degradation of certain intracytoplasmic aggregate-prone
proteins, like mutant huntingtin, by upregulating autophagy in cell culture
(Ravikumar B, et al., Hum. Mol. Genet. 11:1107-17, 2002).
Subsequently, we provided proof-of-principle for this approach in
transgenic fly and mouse models of the disease (Ravikumar B, et al.,
Nature Genetics 36: 585-95, 2004). The potential of this approach has
led to a rapid expansion in our efforts to understand mammalian autophagy
in the context of these diseases.
Where do you see your research leading in the
My aim is to develop the safest possible ways to be able to enhance the
degradation of intracytoplamic aggregate-prone proteins that cause disease
over long periods, as we believe that this would be a rational and
potentially plausible therapeutic strategy for a range of neurodegenerative
Do you foresee any social or political implications for
I would be very happy if we could contribute to helping patients and
families with these devastating conditions.
David C. Rubinsztein, M.B. Ch.B., B.Sc. (Hons), Ph.D., FRCPath.,
Professor of Molecular Neurogenetics
Wellcome Trust Senior Fellow in Clinical Science
Hon Consultant Department of Medical Genetics
Cambridge Institute for Medical Research
University of Cambridge
Keywords: protein degradation pathways in neurodegenerative
diseases, aggregate-prone proteins, parkinson's disease, huntington's
disease, intracytoplasmic aggregate-prone proteins, mutant huntingtin,
upregulating autophagy in cell culture.