Can We Undo the Course of Neurodegenerative Disease?

Columbia professor Rene Hen, Ph.D., called his former student Ai Yamamoto, Ph.D. , “one of the new young stars of Columbia University.” In describing her research into neurodegenerative disease, he cited “remarkable discoveries that have generated enormous hope.”

Following her mentor at Wednesday’s event, hosted by the University’s Mind Brain Behavior Institute and sponsored by the Dana Foundation, Dr. Yamamoto expressed gratitude for these generous words, but also trepidation. “You know those movie trailers that are really good, and then you go and see the movie and are disappointed? There’s a bit of pressure here…”

Yamamoto had little to worry about. The fascinating developments she recounted suggested the possibility not only of arresting the onslaught of diseases like Huntington’s disease (HD), Parkinson’s disease (PD), and Alzheimer’s disease (AD), but of undoing the damage done.

Her research has focused on Huntington’s disease, an inexorable progression of motor impairments, cognitive deficits, and psychiatric deterioration. It’s a terrible affliction for some 30,000 Americans. “But there are worse diseases—Alzheimers and Parkinson’s are equal in devastation and affect more people [3 million and one million]. Why study something so rare?” Yamamoto asked.

For one thing, these and other neurodegenerative diseases have much in common, from symptomatology to pathophysiology, she said. And Huntington’s has a characteristic that makes it an ideal place to start—simplicity.

The origins of AD and PD are complex and obscure. A few rare cases can be pinned on specific genes, “but the majority are sporadic, which means we’re not sure what caused them—genetics, environment, or both. It’s very different in HD: one mutation in one gene. Every single patient has [the gene], and everyone with the mutation develops the disease,” Yamamoto said.

“We know the root cause of HD. So we focus on it with the hope that we can apply our findings to other, more prevalent diseases.”

She described how, 20 years ago, a team of 50 geneticists determined the flaw behind Huntington’s to be an “expansion mutation”— a sequence of nucleotides in the HD gene repeated too many times, which generates a toxic form of the protein huntingtin.

The decades since have illuminated the cascade of molecular mishaps behind this toxicity. Central to the damage, many contend, is the mutant protein’s tendency to form aggregates, “globs of gunk” that accumulate in the neuron.

What makes this especially interesting, Yamamoto said, is that Parkinson’s disease, Alzheimer’s—in fact, every adult-onset neurodegenerative disease—features similar aggregates. Different proteins, same “globs of gunk.”

To better study HD, she continued, researchers genetically modified a mouse to express the mutant gene that makes toxic huntingtin; the mice manifested HD-like symptoms that worsened over time.

Yamamoto wondered: what happens if you stop the process? Would the disease keep moving or stop in its tracks? So she and colleagues developed a toxic huntingtin gene with an on/off switch. While it was on, the mice developed symptoms that worsened right on schedule. Sixteen weeks after it was switched off, the mice had actually gotten better.

What’s more, the signature huntingtin aggregates had all but disappeared from the neurons. “This was a surprise. We had thought they were like rocks, indissoluble… Somehow, the brain had been able to fix itself. It got rid of the toxic protein, and everything went away.”

Thus the “enormous hope” with which Dr. Hen had begun the evening. “Prior to this, everyone wanted to believe we could cure HD or AD,” Yamamoto said. “This was the first demonstration that the possibility existed. It was extremely promising, extremely exciting,”

This promise has inspired a spate of new research. For one thing, she said, efforts to silence the mutant gene have engaged a major pharmaceutical company.

Recent research in her lab focused on eliminating the toxic huntingtin aggregates. The mouse experiment showed that neurons themselves have this capacity. “We didn’t give them any meds, they did it on their own. We want to understand how, and how to make it so they do it all the time.”

The answer may involve the natural process of autophagy, “self-eating,” by which membrane structures in the cell engulf and degrade unwanted proteins, and recycle their amino acids. “Our goal has been to make toxic aggregates the preferred structure for them to eat.”

Yamamoto described a naturally occurring compound called Alfy (autophagy-linked FYVE protein), that can be used to mark aggregates for autophagy. In one experiment, Alfy labeling cut the number of cells with aggregates in half.

On her lab’s agenda: genetically modify mice to make Alfy as well as mutant huntingtin, and see if labeling reverses disease. “Then do it with PD mice, then AD mice.”

What if patients’ neurons were induced to something similar? “Eliminating the aggregates will eliminate these diseases: that’s the hypothesis driving our lab,” she said.

– Carl Sherman

Carl Sherman is a science writer in New York City.

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