FEATURE — Spring 2005

Professor Alison Goate's genetic studies help pinpoint causal pathways that will lead to molecular targets for new drugs (such as enzyme inhibitors or even vaccinations).

Untangling Genetic Roots of Disease

With equal intensity, Professor Alison Goate searches for genetic mutations responsible for several neuropsychiatric disorders, including Alzheimer's disease, alcoholism, and amyotrophic lateral sclerosis.

by Judy H. Watts

To call internationally known molecular geneticist Alison Goate exceptional is not to simply state the obvious. Much like the elusive disease risk factors she finds at the most fundamental level, evidence comes in many forms and is sometimes unexpected. Take the comment by Goate's longtime collaborator and compatriot John Hardy, now chief of the Laboratory of Neurogenetics at the National Institutes of Health's National Institute on Aging. He recruited Goate in 1987 to join his Alzheimer's research lab at London's Imperial College, when she was a young postdoc and both were still in their homeland. Hardy's phrasing is exuberant and his meaning plain: "Alison is fab—as a scientist and as a person! You know, a lot of scientists have got personality disorders of one sort or another, and Alison just hasn't. Everybody trusts her."

A member of the Departments of Psychiatry and Genetics at Washington University School of Medicine since 1992, Goate is the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry and professor of genetics and of neurology. Her 16-person lab is devoted to genetic research on Alzheimer's disease (AD), tauopathies, and alcoholism—and since January 2005, the molecular underpinnings of amyotrophic lateral sclerosis (ALS), often referred to as Lou Gehrig's disease. Her genetic studies help pinpoint causal pathways that will lead to molecular targets for new drugs (such as enzyme inhibitors or even vaccinations).

"The breadth of Alison's research, much of it groundbreaking, is unusual in science," notes alcoholism research colleague Tatiana Foroud, director, Division of Hereditary Diseases and Family Studies in the Department of Medical and Molecular Genetics at Indiana University School of Medicine.

Thanks to Goate's tireless efforts to identify genetic risk factors from an almost unimaginably convoluted labyrinth of genetic and environmental variables—the proverbial needle in a haystack—she has already made huge contributions to understanding diseases that ravage adults of all ages. "She is an absolutely outstanding scientist," says David M. Holtzman, the Andrew B. and Gretchen P. Jones Professor of Neurology and head of the Department of Neurology. He is also the Charlotte and Paul Hagemann Professor of Neurology and Molecular Biology and Pharmacology.

A first—on behalf of early-onset Alzheimer's disease
Goate's name was heard around the world in 1991, when as part of the Hardy lab she became the first person to discover a genetic mutation linked to an inherited form of AD. Just before that breakthrough, researchers including Goate had reported a linkage between familial AD and chromosome 21, as well as the location of the amyloid precursor protein gene (APP) on that chromosome. The protein, amyloid beta 42 (Ab42), is found in plaque deposits in Alzheimer patients' brains. Because scientists back then assumed a single gene caused all early-onset cases of AD, when one group sequenced the APP gene in AD cases from two AD families that had no mutations, most researchers began to look elsewhere on chromosome 21.

Goate, however, was co-investigator on a large study of many families; the data suggested that familial AD was genetically heterogenous—genes on 21 and other chromosomes might be risk factors in different families. In an important conceptual advance, Goate realized that linkage data from multiple families should not be combined unless each individual family provided evidence for linkage to the same chromosome; instead, families had to be examined one by one. She did that—and found APP gene mutations in several families showing linkage to chromosome 21. "It was tremendously exciting!" she says.

At Washington University the following year, Goate continued to investigate early-onset cases that occur without an APP mutation, gathering family material with the help of the Alzheimer's Disease Research Center. In summer 1995, a Toronto lab announced a novel mutation-carrying gene, now called presenilin-1; that fall, Goate and Hardy published a paper that fleshed out the new gene's character.

New Hope for Sufferers of ALS
In January 2005, Alison Goate entered a third research frontier: the genetics of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease that gradually destroys motor neurons reaching from brain to spinal cord to muscles. Although it typically occurs after the age of 40, young adults can be affected as well. Goate will work on ALS with colleagues across disciplines at the new Hope Center for Neurological Disorders at Washington University, which is dedicated to highly collaborative basic science research that will advance the understanding and treatment of a range of conditions. Initially Goate will study one family in which evidence suggests that it may be an X-linked disorder—one carried by females but which typically appears in males. The center is a partnership between Washington University and ALS Hope - The Chris Hobler/James Maritz Foundation.

Other major contributions were Goate's co-authorship of a paper describing a linkage to chromosome 17 in frontotemporal dementia (FTD)—which has its own set of symptoms, can be familial, and can appear before the age of 60. In a 1998 study, Goate and two other groups identified mutations in the tau gene, which codes for the protein that accumulates in tangles inside brain cells in several neurodegenerative diseases including FTD and AD. The finding helped settle a prolonged debate in the field about which of the two characteristic brain abnormalities represented the driving force in Alzheimer's—neurofibrillary tangles or amyloid plaque deposits. The study showed that tau gene mutations produce dementia and tangles but not B-amyloid deposition—and therefore, not AD.

"As the mutations in APP and presenilin were already saying," explains Goate, "abnormal accumulation of B-amyloid drives Alzheimer's disease pathology. Tangle formation is a secondary event; when it is primary, frontotemporal dementia occurs." Goate's lab continues to work on the genetics of other tangle-associated disorders such as progressive supranuclear palsy.

The quest to untangle late-onset disease
Since 1997, Goate has been working on the recalcitrant genetics of late-onset AD, the more common form, which affects about 4 million Americans over 65. The only known genetic risk factor for that is the e4 allele of the apolipoprotein E (ApoEe4) gene on chromosome 19, which increases risk by three to eight times. But since only half of patients carry ApoEe4 alleles, other factors must be involved. In 2000, Goate led an international team of researchers that identified linkage to chromosome 10 suggesting that a gene in the region is a risk factor for AD. "Frustratingly, we're still working on trying to find that and other genes involved in late-onset Alzheimer's disease," says Goate.

She is emphatically optimistic, however. "Because of the Human Genome Project's advances, we have powerful tools to attack these problems. We will resolve this."

Another first—for alcoholism and depression
Goate focuses with equal intensity on two other insidious diseases affecting millions of Americans—alcoholism and depression. She is lead investigator on a national team including School of Medicine psychiatric geneticists that recently became the first to identify a specific "susceptibility" gene that appears to increase the risk for both disorders.

Goate's team analyzed DNA from 2,310 people from 262 families in which at least three members were alcoholics. Genetic linkage analysis in these families identified a region on chromosome 7 that was linked to risk for both alcoholism and depression. Because other researchers from the Collaborative Study on the Genetics of Alcoholism (COGA) had found that abnormal electrical activity in the brain might signal a risk for alcoholism and linked those patterns to a gene on chromosome 7 called CHRM2, Goate's team started there. They believe that normal variations in CHRM2 either protect or put a person at risk, and will next identify the DNA sequence variants and figure out how they change the involved proteins' functions.

Goate's ongoing work, which will establish the molecular basis for the anecdotal connection between alcoholism and depression, is part of the six-university, NIH-funded COGA. "Our work is going very well!" Goate says. "The multidisciplinary COGA team has already identified several genetic risk factors for alcoholism." COGA colleague Foroud says simply: "Alison's contributions in this endeavor will be as far-reaching as what she has already done for understanding Alzheimer's disease."

A dedicated mentor, Professor Goate (left) works with Emily Walker, a graduate student in biochemistry, who is researching the cell biology of Alzheimer's disease.

A true collaborator and mentor
Goate has distinguished herself in important areas unrelated to her research. "She has mentored a cadre of young scientists," Foroud says. "Many scientists don't do that." She was president of the Academic Women's Network in 2003-04 and works hard to support women faculty and junior faculty in particular. She has "done incredibly well" and still remains "a normal person," says her mentor, John Hardy, with whom Goate shared the prestigious Potamkin and MetLife research awards. "If I ever have a difficult scientific problem or a situation in my lab, she gives me fair advice. She's a great mum [who takes her children to school every morning, picks them up many afternoons, and saves her own homework until after they're in bed]; she has two lovely daughters [Juliet, 13, and Sasha, 9]; and she has a great husband [physician Frank Ashall]," Hardy says. "She's just a great person!"

And from David Holtzman, one final distinction: "This is important, because it's very uncommon: Alison is universally admired. Everybody says exactly the same things!"

Judy H. Watts is a free-lance writer based in Santa Barbara, California, and a former editor of this magazine.