HD Cell Death Mechanisms

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 incl

Nov 27, 2000
Eugene Russo

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)

To identify potential therapeutic targets for Huntington's disease (HD), an inherited, dementia-inducing neurodegenerative condition, researchers need a better understanding of the role that huntingtin protein plays in cell death. Michael Greenberg's group at Harvard Medical School chose to investigate the underpinnings of HD cell death based on their research into the signaling pathways that inhibit cell death machinery.

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.


Michael Greenberg
To link these pathways to the disease, Greenberg's lab developed a cellular model using rat striatal neurons because HD causes neuronal death primarily in the brain's striatum. But their model differed significantly from previously developed models. HD in vitro models generally involve overexpressing mutant or wild type huntingtin in a normal cell line. But studying the specific path to cell death in these nonneuronal models can be tricky; the investigator cannot know whether death results from a mechanism that's actually employed in the disease or to aspects of the mechanism not conserved in the HD-affected neuron. Greenberg's model used cells that routinely die as the result of HD.

"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 erusso@the-scientist.com.

References

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.