The Tangles of Neurodegeneration Not Easy to Unravel

It’s easy to think a neuron is a neuron is a neuron. But the various neurodegenerative diseases seem to focus on a specific group of neurons while sparing the others.

Alzheimer’s disease damages the hippocampus, the seat of learning and memory. Parkinson’s disease destroys dopamine-producing cells in the substantia nigra, in the midbrain. Huntington’s disease attacks the striatum, alongside the thalamus in the center of the brain. Frontotemporal dementia, often mistaken for Alzheimer’s, damages the frontal lobes, producing bizarre and often inappropriate behavior, but usually spares memory. Amyotrophic lateral sclerosis, more commonly known as ALS or Lou Gehrig’s disease, affects the motor neurons that control muscle contraction. If a neuron is a neuron, how do these forms of neurodegeneration distinguish neurons in one part of the brain from neurons in another?

“A neuron isn’t a neuron,” says Dennis W. Dickson, a professor of pathology at the Mayo Clinic in Jacksonville, FL, and co-editor, with Dr. Roy O. Weller, of Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders. “Neurons are different in terms of where they are in the brain and where they project. Neurons are different in terms of their neurotransmitters.”

So how do these differences translate into susceptibility to the various forms of neurodegeneration? Dickson, one of the leading experts on the subject, doesn’t really know.

“At one point we thought there might be a simple explanation based on the neurotransmitter involved,” he said. “For example, Alzheimer’s disease was thought to be a defect in cholinergic neurons, Parkinson’s disease in the dopaminergic neurons, and so on. But this proved to be too simplistic. I don’t think anyone has a good handle on it. We know that neurons form interconnected systems or networks, but why one network fails in one disorder and some other network in another disorder is unknown.”

As with many diseases, genetic factors undoubtedly play a role. Huntington’s disease, for example, results from a mutation in the gene for huntingtin protein. Inherit the mutation and you will get the disease.

But genes that contribute to other forms of neurodegeneration merely increase the risk of developing the disorder: A person’s interaction with the environment, or plain bad luck, will determine whether or not the disease develops. Head injuries seem to contribute to Alzheimer’s, and exposure to certain pesticides seems to contribute to Parkinson’s, but people who carry risk genes for those disorders may not succumb to them. And some people develop neurodegeneration for no apparent reason. Those cases are called idiopathic—cause unknown.

Understanding some forms of neurodegeneration is growing, if in small increments. Dickson and his co-authors had to make substantial revisions in the information about frontal lobe dementia (FTD) while preparing the second edition of Neurodegeneration, recently released.

“In first edition of the book there were no major genetic causes known in FTD other than mutations in tau protein, but most cases didn’t involve tau,” Dickson said. “The protein involved in most frontal lobe dementias is TDP-43. That was discovered after the first edition of the book was published in 2006.” And neurodegeneration may involve more than neurons. “The role of glia in neurodegenerative disorders is also increasingly recognized,” he writes in his introduction to the book.

So what does the future of research hold?

In a lecture titled, “Neurodegenerative Diseases: The Path to Therapy,” delivered at the recent meeting of the Society for Neuroscience in Washington, DC, Anne Young provided a bird’s-eye view of modern knowledge about the various diseases that cause neurons to die, and she offered predictions on where research is headed. Young is Julieanne Dorn Professor of Neurology at Harvard Medical School, Director of the MassGeneral Institute for Neurodegenerative Diseases, and a member of the Dana Alliance for Brain Initiatives.

Although descriptions of neurodegeneration go back to ancient Egypt and China, she observed, modern descriptions that capture the most conspicuous symptoms didn’t emerge until the 19th century. James Parkinson, for example, published “An Essay on the Shaking Palsy” in 1817 based on a handful of cases, some of whom he stopped on the street and examined. Jean-Martin Charcot identified what is known today as amyotrophic lateral sclerosis (ALS) in 1869. George Huntington published “On Chorea,” his detailed description of the disease that bears his name, in 1872. And in 1907 Alois Alzheimer published his account of what became known as Alzheimer’s disease.

Swedish scientist Arvid Carlsson’s discovery in the 1950s that L-dopa could alleviate Parkinson’s symptoms triggered the idea that adding something to deficient neurotransmitters might solve other forms of neurodegeneration, which almost always disrupt at least one neurotransmitter, Young said. Acetylcholine, for example, declines in Alzheimer’s disease. Huntington’s and Alzheimer’s both result in impaired uptake of glutamate. Frontotemporal dementia often produces deficits of serotonin and dopamine, but usually not of acetylcholine.

But researchers have found that adjusting neurotransmitter levels does little to halt the destruction caused by neurodegeneration; L-dopa merely delays degeneration.

“When you look at what’s available in our armamentarium to treat neurodegenerative disease patients, all the therapies are based on the transmitter era of decades ago,” Young observed. “So we have cholinesterase inhibitors, dopamine agonists and antagonists, glutamate antagonists, GABA antagonists. But we haven’t been able to come up with better therapies.”

The human genome is helping scientists untangle some genetic causes of neurodegeneration. Young participated in the landmark study begun in 1979 by Nancy Wexler at Columbia University of a large extended family living around Lake Maracaibo in Venezuela. Many family members carry the gene for Huntington’s, and their DNA helped researchers determine that the mutation that causes the disease is located on chromosome 4.

“Many of the techniques used to find the gene for Huntington’s disease were used by others to find genes for cerebellar ataxias, ALS, and Alzheimer’s disease,” Young said. “Then, in 2001 when the human genome was sequenced, it became possible for many neurodegenerative diseases to be studied in detail genetically. Genes could be put into drosophila and other models that would mimic human diseases, and markers of the multiple pathways affected have been found. Genetics has transformed our knowledge of these diseases.”

Although the various forms of neurodegeneration focus on different parts of the brain, they have one thing in common, Young said. “All neurodegenerative diseases have aggregates. All seem to involve small protein monomers that become misfolded, and these aggregate into oligomers.” The plaques found in the brains of Alzheimer’s patients, for example, consist of oligomers of amyloid precursor protein that have stuck together, forming clumps between neurons.

Paradoxically, these clumps may be less toxic than the separate fragments themselves, and might represent the brain’s attempt to protect itself from damage. “This suggests two strategies,” Young said. “Try to keep misfolded monomers from happening in first place, and then drive the oligomers into aggregates. Both may be therapeutically effective.”

Another theory gaining attention views neurodegeneration as a type of prion disease such as Creutzfeld-Jacob disease or mad cow disease. In such diseases a misfolded protein somehow induces similar misfolding in other proteins, creating a chain reaction that can spread through the nervous system.

“One could attack this pharmacologically by looking for drugs that inhibit the release and uptake of these misfolded proteins,” Young said.

An effective attack on neurodegeneration will require the development of techniques to detect biomarkers of disease, such as the accumulation of amyloid-beta protein in Alzheimer’s disease, or the appearance of alpha-synuclein protein in Parkinson’s, Young said. The earlier these diseases are discovered the better, but the most encouraging development she can see is the potential to reverse neurodegeneration after it has begun.

“We think these diseases are reversible,” she said. “We don’t want to just slow the disease. We’d rather delay its onset and, even better, take people who are early symptomatic and reverse the disease. We can make a difference in your lifetime.”

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