The Disordered Mind

by Eric R. Kandel

  One alternative was surgery. The first effective surgical treatments for Parkinson’s disease were undertaken 150 years after Parkinson first described the disorder, by neurosurgeons desperate to help patients with uncontrollable, excessive tremor and limited movement. The surgeons identified, largely by trial and error, specific regions of neural circuits in the basal ganglia and the thalamus that are responsible for the tremor and alleviated their patients’ symptoms by destroying those regions.

  During the 1970s and ’80s, great progress was made in understanding the anatomy and physiology of the motor system, mostly by Mahlon DeLong, then at The Johns Hopkins University and now at Emory University. He found that a particular area of the basal ganglia, the subthalamic nucleus, is also rich in dopamine-producing nerve cells and plays an essential role in the control of movement.8

  Just as DeLong was working on the subthalamic nucleus, a new drug, billed by dealers as “synthetic heroin,” showed up on the street. This drug was contaminated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a substance that causes the slowness of movement, tremor, and muscular rigidity typical of Parkinson’s disease. After some young people who had taken the drug died, autopsies revealed that MPTP had destroyed the subthalamic nucleus, and with it the brain cells that produce dopamine. Such damage could not be reversed in survivors, but they did respond positively to L-dopa.

  Scientists then used MPTP to create a monkey model of Parkinson’s disease. They expected to find that the destruction of dopamine-producing cells resulted in underactivity of the subthalamic nucleus, leading to the symptoms of Parkinson’s disease. But when DeLong started to record electrical signals from single neurons in the subthalamic nucleus of the monkeys, he found something quite different: the neurons were abnormally active. To his astonishment, the symptoms of Parkinson’s disease were caused not by decreased activity of these neurons but by an abnormal increase in activity.

  To test whether this abnormal activity was responsible for the tremor and rigidity of Parkinson’s disease, DeLong destroyed the subthalamic nucleus in one side of the brain, thus halting the abnormal activity. In 1990 he published the amazing result: damaging the subthalamic nucleus in one side of the brain of a monkey with Parkinson’s disease caused the tremor and muscular rigidity on the other side of the body to vanish.9

  DeLong’s discovery led Alim-Louis Benabid, a neurosurgeon at the Joseph Fourier University in Grenoble, France, to start thinking about using deep-brain stimulation to treat people with Parkinson’s. Deep-brain stimulation, as we have seen, involves implanting electrodes in the brain and a battery-operated device elsewhere in the body. The device sends high-frequency electrical impulses into a neural circuit, in this case the subthalamic nucleus. The impulses essentially inactivate the circuit, much as the damage to the monkey’s subthalamic nucleus did, thus preventing the abnormal activity from interfering with controlled movement (fig. 7.3). The treatment is adjustable and reversible.

  By the 1990s, deep-brain stimulation had virtually replaced all other surgical treatments for Parkinson’s disease. It does not work for everybody, and it is not a cure: it treats only the symptoms of the disease. If the battery sending electrical impulses should fail or the wires become disconnected, which happens only rarely, the benefit of the treatment is lost almost immediately.

  Figure 7.3. Deep-brain stimulation

  Deep-brain stimulation has also been used successfully to treat people with psychiatric disorders such as depression. Instead of stimulating the motor circuit to alleviate the symptoms of movement disorders, electrical pulses stimulate the brain’s reward system to alleviate the symptoms of depression. Thus deep-brain stimulation may ultimately prove to be a treatment for specific neural circuits rather than for specific diseases.

  HUNTINGTON’S DISEASE

  Approximately thirty thousand people in the United States have Huntington’s disease, a disorder that affects both sexes equally. The age at which the disease first appears varies widely, but the average age of onset is forty. The disorder was first described in 1872 by George Huntington, a Columbia University–trained physician who noted the hereditary nature, involuntary movements, and changes in personality and cognitive functioning that characterize the disorder. His description was so clear and so accurate that other physicians could readily diagnose the disorder, and they named it after him.

  Unlike Parkinson’s disease, which is fairly localized at first, Huntington’s disease can become more widespread quite early and can lead to cognitive as well as motor defects, including sleep disorders and dementia. It primarily affects the basal ganglia, but it also affects the cerebral cortex, the hippocampus, the hypothalamus, the thalamus, and occasionally the cerebellum (fig. 7.4).

  Figure 7.4. Huntington’s disease affects the basal ganglia soon after onset and later spreads throughout the cortex.

  It took many years to make progress against Huntington’s disease, but in 1968 a well-known psychoanalyst—Milton Wexler, whose wife had developed the disease—founded the Hereditary Disease Foundation. Wexler had a dual purpose in mind: to raise funds for basic research and to organize a scientific workforce to focus research on Huntington’s disease. This foundation has had a major impact in advancing our understanding of the disease.

  Since Huntington’s disease is hereditary, the early focus of the foundation was on finding the critical gene. In 1983 David Housman and James Gusella used a new strategy, called exon amplification, to localize Huntington’s disease to a gene on the tip of chromosome 4; they named the gene huntingtin.10

  Ten years later, an international collaborative group called the Gene Hunters, organized by the Hereditary Disease Foundation, finally isolated and sequenced the mutant huntingtin gene.11 Once the gene was isolated, it could be inserted into a worm, a fly, or a mouse to see how the disease would progress. The Gene Hunters noticed that one portion of the huntingtin gene is larger than normal. This portion is called a CAG expansion, and it is what causes the disease.

  Figure 7.5. Long strings of CAG in a protein cause it to clump inside the cell, becoming toxic. The risk of Huntington’s disease increases with the number of CAG repeats.

  Our genes are essentially an instruction manual written in a four-letter alphabet: C (cytosine), A (adenine), T (thymine), and G (guanine). Each word is made up of three letters. The word CAG codes for the amino acid glutamine and calls for it to be inserted into a protein when that protein is being synthesized. In Huntington’s disease, a portion of the mutant gene repeats the word CAG again and again, resulting in the insertion of too many glutamines. This expanded string of glutamines causes the protein to clump inside the neuron, killing the cell. We all have multiple CAG repeats in this portion of the huntingtin gene, but a person who inherits a mutated version of this gene and, as a result, has more than 39 CAGs will develop Huntington’s disease (fig. 7.5).

  Before long, ten other diseases were discovered to have this CAG expansion, including fragile X syndrome, several distinct forms of spinocerebellar ataxia, and myotonic dystrophy. All of these diseases affect the nervous system, all of them involve misfolded proteins that form clumps, and all of them cause cell death.

  COMMON FEATURES OF PROTEIN-FOLDING DISORDERS

  We now know that the core molecular cause of Parkinson’s disease and Huntington’s disease resembles that of several other neurodegenerative disorders: Creutzfeldt-Jakob disease, Alzheimer’s disease, frontotemporal dementia, chronic traumatic encephalopathy (the progressive brain degeneration seen in people who have suffered repeated concussions), and the genetic form of amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). All of these diseases result from abnormally folded proteins that form clumps in the brain, becoming toxic and eventually killing neurons (fig. 7.6).

  In 1982, Stanley Prusiner of the University of California, San Francisco, announced a remarkable discovery: an infectious, abnormally folded protein is involved in Creutzfeldt-Jakob disease, a rare, degenerative brain disorde
r.12 Prusiner called this protein a prion.

  Figure 7.6. Abnormally folded proteins form clumps in the brain, leading to neurodegenerative disorders.

  Prions are formed when normal precursor proteins misfold. In their normal conformation, precursor proteins mediate healthy cellular functions and are everywhere in the brain. Neurons, like other cells, have internal mechanisms that monitor the shape of proteins. Usually these mechanisms compensate for mutations or damage to the cell, but as we age the mechanisms become weaker and less effective at preventing shape changes. When that happens, a mutant gene or damage to the cell can cause normal precursor proteins to misfold into a lethal prion conformation. The prions form insoluble clumps inside the neuron, disrupting its function and eventually killing it (fig. 7.7).

  What makes prions so unusual—and so dangerous—is their ability to self-propagate. In other words, prions do not need genes in order to replicate. As a result, these misfolded proteins are essentially infectious. They can be released by affected neurons and taken up by neighboring cells, where they induce normal precursor proteins to fold abnormally, becoming prions and ultimately killing the cells (fig. 7.8).

  Figure 7.7. Age-dependent prion formation: mutant precursor proteins can cause normal proteins to change shape.

  Figure 7.8. Misfolding changes normal precursor proteins into prions, which then form toxic clumps in the brain.

  Learning how prions form opened up new possibilities for research directed toward preventing or reversing protein misfolding. Currently, there are no drugs that slow brain degeneration, but prion formation presents three points at which such an intervention might be possible: (1) the point at which a normal precursor protein folds into a prion form, (2) the point at which the prion form aggregates into fibers, and (3) the point at which plaques, tangles, and bodies form (fig. 7.9).

  Prusiner’s astonishing observations about prions—that they can reproduce and infect other cells, yet contain no DNA—were initially met with considerable resistance in many scientific quarters. But in 1997, fifteen years after discovering these self-replicating, misfolded proteins, Prusiner was awarded the Nobel Prize in Physiology or Medicine. In 2014 he wrote a book about his experiences during those years:

  I wrote this book because I feared that neither science historians nor journalists could construct an accurate narrative of my investigations. This is a first-person account of the thinking, the experiments, and the surrounding events that led to the identification of infectious proteins, or “prions” as I named them. I have tried to describe what appears in retrospect to be an audacious plan to define the composition of the agent that causes scrapie, a barnyard disease whose etiology was a mystery at the time. On many occasions, I worried that my data might lead me down dead-end paths. Despite my fascination with the problem, I was haunted by a fear of failure; my anxiety was palpable at almost every turn. Was the problem intractable? As small successes emerged, so did a legion of naysayers who questioned both the wisdom of my pursuit and my scientific prowess; indeed, there were times when little but my naïveté and exuberance sustained me.

  Figure 7.9. Three points of possible intervention to prevent or reverse protein misfolding

  The skeptical and frequently hostile reactions to prions from many precincts of the scientific community reflected resistance to a profound change in thinking. Prions were seen as an anomaly: they reproduce and infect but contain no genetic material—neither DNA nor RNA; thus they constitute a disruptive transition in our understanding of the biological world. The consequences of the prion discovery are immense, and they continue to expand. Their causative role in Alzheimer’s and Parkinson’s diseases has important implications for the diagnosis as well as the treatment of these common, invariably fatal maladies.13

  GENETIC STUDIES OF PROTEIN-FOLDING DISORDERS

  Drosophila, the fruit fly, is the invertebrate animal model par excellence. It was first developed as an experimental organism by Thomas Hunt Morgan at Columbia University to study the basic function of chromosomes in heredity. Later, Seymour Benzer focused on genes that are involved in behavior. He found that genes work together in complex networks called gene pathways.

  In many diseases, fruit flies and people share not just genes but entire gene pathways. Scientists use these shared features, which have been conserved through the course of evolution, to gain crucial insights into human disease, including neurological disorders. One advantage of using flies is that it speeds up the research process. A disease like Parkinson’s can take decades to appear in people, but it will take only days or weeks to appear in flies. A key gene that is mutated in Parkinson’s disease, synuclein alpha, or SNCA, was first identified in the fruit fly (fig. 7.10).

  Parkinson’s disease usually occurs spontaneously, for reasons that are still not known, but several factors play a role, including the patient’s genes (certain gene variants are thought to increase the risk of Parkinson’s disease) and exposure to certain toxins. In its rare inherited forms, the SNCA gene is mutated, resulting in excessive amounts of the alpha-synuclein protein in the brain, in misfolded alpha-synuclein proteins in the brain, or both. Since all Parkinson’s patients, even those who did not inherit the disease, have one or both of these protein abnormalities in the brain, scientists concluded that the mutated gene might reveal some general aspect of the disease.

  It turns out that the protein produced by the mutated gene is the main component of Lewy bodies. These bodies are the toxic clumps that form inside neurons when the alpha-synuclein protein folds abnormally.

  Researchers inserted the mutated SNCA gene into the dopamine-producing neurons of the fruit fly brain to see what would happen. They knew that dopamine is essential to muscle control and that insufficient dopamine causes the palsy and other abnormal movements characteristic of Parkinson’s disease. The scientists found that by inserting the mutated gene, they had compromised the dopamine-producing neurons’ ability to function. The result was behavioral effects in flies that are strikingly similar to the effects of Parkinson’s disease in people.14

  Flies, like people, have conserved molecular pathways—called molecular chaperone pathways—that help proteins take on their normal shape and that sometimes even reverse misfolding. By helping proteins to fold properly, the chaperone pathways prevent clumping. Scientists wondered what would happen if they gave the flies more of the helper proteins that act in these pathways. Perhaps the presence of more helper proteins would encourage the normal folding of alpha-synuclein proteins and the healthy production of dopaminergic neurons.

  Figure 7.10. The brain of the fruit fly with normal alpha-synuclein protein (top); alpha-synuclein protein produced by a mutated gene (center); and the mutant protein with the helper protein Hsp70, which promotes normal refolding (bottom). Dopamine-producing neurons are indicated by arrows.

  By adding helper proteins, the dopamine-producing neurons were no longer compromised. Chaperone proteins have also been found to protect against movement disorders: flies with a mutant SNCA gene are poor climbers, but when flies with the same mutation overexpress chaperone proteins they are able to climb normally. This technique also works in fruit fly models of other neurodegenerative diseases—of which there are many now—as well as in mouse models of some neurodegenerative diseases, illustrating once again the utility of animal models for the study of human disease.

  LOOKING AHEAD

  Parkinson’s and Huntington’s diseases, Alzheimer’s and frontotemporal dementia, Creutzfeldt-Jakob disease, and chronic traumatic encephalopathy all produce widely varying effects on our thinking and behavior, our memory and emotions. Yet we now know that these and other neurodegenerative disorders share an underlying molecular mechanism: the failure of proteins to fold correctly, thus eventually killing neurons.

  We also know that the function of any given protein is determined by its unique shape, a shape arrived at through an extraordinarily precise process of folding. Thus, the dramatically different symptoms caused by protei
n-folding disorders are attributable to changes in the shape of particular proteins responsible for particular functions in the brain. As we have seen, the death of dopamine-producing neurons, caused by misfolded proteins, leads to Parkinson’s disease. A mutant gene that orders up too many glutamines during protein synthesis results in misfolded proteins that clump in the brain and cause Huntington’s disease, as well as several other diseases of the nervous system. The self-replicating, misfolded proteins known as prions, which are responsible for the toxic tangles found in Creutzfeldt-Jakob and related diseases, can even act as infectious agents.

  At present, there are no drugs that slow brain degeneration, although deep-brain stimulation can calm the neural circuits responsible for uncontrolled movement, thereby giving relief to people with Parkinson’s disease. Research on neurological disorders now includes genetic and molecular studies, which may provide scientists with points of entry for preventing or reversing the process of protein misfolding. As we have seen, genetic studies in animal models are already beginning to move us toward that goal.

  8

  THE INTERPLAY OF CONSCIOUS AND UNCONSCIOUS EMOTION: ANXIETY, POST-TRAUMATIC STRESS, AND FAULTY DECISION MAKING

  When we shop in a supermarket or chat with strangers at a party, we unconsciously rely on our emotions to help us navigate the situation. We also rely unconsciously on our emotions when we make decisions. Emotions are states of readiness that arise in our brain in response to our surroundings. They give us critical feedback about the world and set the stage for our actions and decisions. In chapter 3, we considered emotion in the context of mood, our individual temperament—specifically, we considered what the biology of mood disorders has revealed about our sense of self. In this chapter, we examine the nature of emotion—its conscious and unconscious components—and the essential role it plays in other aspects of our life.