|For this article, Eugene Russo interviewed Michael E. Greenberg, a professor of neurobiology and neurology at the Children's Hospital, Harvard Medical School. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. |
F. Saudou, S. Finkbeiner, D. Devys, and M.E. Greenberg, "Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions," Cell, 95:55-66, Oct. 2, 1998. (Cited in more than 175 papers since publication)
In the four years prior to this paper, Greenberg's group had clarified a pathway in which the neurotrophic factors BDNF (brain-derived neurotrophic factor) or insulin-like growth factor 1 (IGF-1) activate a cascade that includes the phosphoinositide 3-kinase (PI3-K) and the serine-threonine kinase Akt. The cascade culminates with the phosphorylation of the BCL-2 family member BAD and the suppression of apoptosis, or programmed cell death.
"We thought that it would be interesting to see if we could apply some of our survival pathways that inhibit the death machinery to models of degeneration ... relevant to human disease," explains Greenberg, professor of neurobiology and neurology at the Children's Hospital, Harvard Medical School. Postdoctoral fellow Frederic Soudou led the efforts; prior to coming to the lab, he had characterized the HD gene.
"We were surprised to find that we could recapitulate a lot of the features of the cell death that's seen in patients," said Greenberg. They saw significant death of striatal neurons that expressed huntingtin proteins with large cytosine-adenosine-guanine (CAG) trinucleotide expansions, a trademark of HD. And as expected, they did not see the same effects in hippocampal neurons. Confident of their model's precision, Greenberg's group investigated the features of HD-induced cell death. They
demonstrated its apoptotic characteristics and also showed that CAG expansion-dependent cell death required huntingtin's presence in the nucleus.
In fact, according to Greenberg's findings, intranuclear inclusions of the protein, which some in the field had suggested were a critical element of the pathway to cell death, were not necessarily a causative agent. His group was one of the first to suggest that the inclusions might be protective rather than toxic. Says Greenberg, "It still remains an open question--whether [intranuclear inclusions] are going to be intimately associated with the death process, or whether they might be actually reflecting the cell's attempt to survive." A paper accompanying Greenberg's findings reported similar conclusions about inclusions in transgenic mice carrying the spinocerebellar ataxia type 1 (SCA1) gene, which causes a neurodegenerative disorder.1
While suggesting that his cellular models are important, particularly for drug discovery, Greenberg also emphasizes the value of transgenic mouse HD models. In one of the latest advances, investigators were able to precisely regulate the expression of the huntingtin protein in a transgenic mouse model.2 They actually observed some recovery with the protein "turned off," raising the possibility that HD may be reversible.
The major focus of Greenberg's work continues to be on the basic mechanisms that promote neuronal survival. However, he and his colleagues have applied their understanding of signaling mechanism to Alzheimer's disease as well. They are currently investigating how AD's characteristic plaque-forming beta amyloid protein induces neural toxicity.
Eugene Russo can be contacted at email@example.com.
1. I.A. Klement et al., "Ataxin-1 nuclear localization and aggregation: Role in polyglutamine-induced disease in SCA1 transgenic mice," Cell, 95:41-53, Oct. 2, 1998.
2. A.Yamamot et al., "A Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease," Cell, 101:57-66, March 31, 2000.