Tuesday, September 10, 2013

Ihn Sik Seong: The Long Search for the Full Story of Huntington’s Disease

Ihn Sik Seong: The Long Search for the Full Story of Huntington’s Disease

Ihn Sik Seong, PhD, is nothing if not patient. And ambitious. It’s a combination that comes in handy when trying to understand the molecular pathogenesis of Huntington’s disease, which has been Dr. Seong’s focus for over a decade.

“The reason understanding HD is so difficult is because of its chronic and cumulative nature,” he says. Although the first clinical symptoms of the disease may not appear until a person’s forties or later, the mutation is present and may be exerting its effects from the earliest stages of development. Given that, “the molecular phenotype and pathophysiology should be very complicated,” he says.

After receiving his PhD in molecular biology from Seoul National University in Korea in 1999, Dr. Seong came to the MGH Neurology department for post-doctoral training with Marcy MacDonald, PhD. He is now Assistant Professor of Neurology at Harvard Medical School and is on the faculty of the Center for Human Genetic Research at MGH.

Dr. Seong got involved in HD research through his expertise in protein structural chemistry and his interest in proteases in cell regulation. “When I was looking for a post-doc, I found a paper on HD, and got excited—here was a single-gene disorder whose major pathogenic mechanism appeared to be the toxic polyglutamine fragment created by a protease.” He thought the best way forward was simply to purify the full-length protein. “I explained my plan to Dr. MacDonald, and she just smiled.  I realized very quickly I was too ambitious! Even cloning the protein of full-length huntingtin is not easy—the bacteria containing full-length huntingtin clone just die in normal cloning conditions.”

But he persisted, and, in collaboration with Dr. MacDonald and James Gusella, PhD, of the Center for Human Genetic Research, Dr. Seong has made headway in studying the full-length protein, which he sees as the key to unlocking the secrets of the disease. “Understanding the structure of full-length huntingtin is very important in understanding its function,” he says, and any model should recapitulate several key features of the human disease. In particular, aspects of the phenotype such as age of onset should be correlated with polyglutamine length. “There should be a series of models, rather than a dichotomous wild-type or mutant. It’s not just on-off; it should be polymorphic.”

Working in the full-length huntingtin model, he and his collaborators have shown that mutation causes a length-dependent defect in mitochondrial ATP production, which in turn reduces cadherin levels in striatal neurons, altering development of neurites, potentially a very early effect of the mutation. Exploring another likely route to disease, he has shown that full-length wild-type protein plays a critical role in organizing an epigenetic gene silencing complex, and in work to be published soon, he has examined the disruption of that function by polyglutamine expansion. “Huntingtin definitely has a role at the beginning of development, which could be a starting point for cumulative pathogenesis,” Dr. Seong says.

His approach to this long, hard problem has been shaped by the example of Drs. MacDonald and Gusella, he says. “Their focus is on understanding the real nature of Huntington’s disease, not just publishing the next paper. As a scientist, I try to follow their model. It’s not easy, and it takes a long time, but that’s what motivates me.”

Striatal neurons expressing full-length mutant huntingtin exhibit decreased N-cadherin and altered neuritogenesis. Reis SA, Thompson MN, Lee JM, Fossale E, Kim HH, Liao JK, Moskowitz MA, Shaw SY, Dong L, Haggarty SJ, MacDonald ME, Seong IS. Hum Mol Genet. 2011 Jun 15;20(12):2344-55.

Huntingtin facilitates polycomb repressive complex 2. Seong IS, Woda JM, Song JJ, Lloret A, Abeyrathne PD, Woo CJ, Gregory G, Lee JM, Wheeler VC, Walz T, Kingston RE, Gusella JF, Conlon RA, MacDonald ME. Hum Mol Genet. 2010 Feb 15;19(4):573-83.

HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Seong IS, Ivanova E, Lee JM, Choo YS, Fossale E, Anderson M, Gusella JF, Laramie JM, Myers RH, Lesort M, MacDonald ME. Hum Mol Genet. 2005 Oct 1;14(19):2871-80.

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