Neurodegenerative Diseases and Brain Injury

Brain disorders are among the most serious health problems facing modern society. Many of these disorders become more common with advancing age, including Alzheimer’s disease, Parkinson’s disease, stroke, amyotrophic lateral sclerosis (ALS), and many others. The burden of these neurodegenerative diseases is growing inexorably as the population ages, with enormous economic and human costs.

Some neurodegenerative conditions, such as Huntington’s disease or familial ALS, have clear genetic causes. Others involve complex interactions of genetic and environmental influences that can affect the brain in many ways. Our work at the McGovern Institute spans the gamut from genetic studies of animal models to imaging studies of human clinical patients. We are working to understand the basic brain mechanisms that are affected by these diseases and to understand how the brain responds to therapeutic interventions. The answers to these fundamental questions will form the foundation for new treatments for these diseases.

The following faculty members are conducting research relevant to neurodegenerative diseases and brain injury:

Bob Horvitz

A major theme of Bob Horvitz’s research is cell death, a central feature of neurodegenerative disease. He studies this process in the nematode worm Caenorhabditis elegans, a tiny organism that despite its simplicity has provided an extraordinary range of insights into general biological principles, many of which are shared with humans. Among the most important is the concept of programmed cell death. Many cells die naturally during the course of development, and Horvitz’s lab has identified the underlying genetic mechanism that controls this process – work for which he shared the 2002 Nobel prize. Horvitz’s work has led to new thinking about cancer mechanisms, and to new therapeutic approaches that are currently in clinical trial. His work may also lead to new treatments for a variety of neurodegenerative diseases, including retinal degeneration, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, stroke, and brain injury. One of his most recent interests is the genetic basis of aging, and a better understanding of this process could help to explain why the risk of so many degenerative diseases rises rapidly with advancing age.

In separate line of work, Horvitz has a longstanding interest in human amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease). He was a principal member of the team that in 1993 identified the first gene to cause familial ALS, and in collaboration with colleagues at Massachusetts General Hospital he continues to search for additional ALS genes.

Guoping Feng

Poitras Professor of Neuroscience Guoping Feng studies the development and function of synapses and their disruption in brain disorders.  Synapses are the sites of neuron-neuron communications. He uses molecular genetics, combined with behavioral and electrophysiological methods, to create animal models in order to understand how disruptions in molecular components of synapses can lead to a disease state. Transgenic mouse-based Alzheimer’s models have moved the field forward significantly, but pathophysiological differences, such as the lack of obvious neurodegeneration, have called the relevance of this model to the human disease into question. The Feng laboratory’s goal is to develop new animal model systems that will provide a better way to study the basic mechanisms and therapeutic strategies of cerebral aging and Alzheimer’s. Feng’s vision is to bring an unprecedented level of genetic selections, genetic manipulations and neural mechanistic studies into a new research model for Alzheimer’s, ideally revealing novel mechanisms and strategies for drug development.

Feng Zhang

The dysfunctions in neurons and their connections underlying Alzheimer’s remains a major hurdle for advancing new therapies. The long term objectives of junior researcher Feng Zhang’s laboratoryare to develop novel technologies that enable researchers to better pinpoint biological mechanisms underlying disease, conduct studies at a much higher throughput, and obtain results with much more confidence.  Recent bioinformatic studies have identified a large list of genetic mutations that are highly correlated with patients suffering from Alzheimer’s. Yet one of the major research challenges lies in the difficulty for testing the causal role of the identified mutations in Alzheimer’s due to the extremely difficulty for obtaining living brain tissue from Alzheimer’s patients.

Current research in the Zhang group focuses on developing new technologies that enable researchers to use stem cells and animal models to screen and identify mutations that can directly lead to Alzheimer’s, without requiring any patient tissue. Using the state-of-the-art genome engineering technologies developed over the past year, Zhang and colleagues can now directly engineer an otherwise healthy stem cell to carry a single mutation implicated in Alzheimer’s. Researchers can compare this engineered mutant stem cell with the healthy cell and determine whether that specific mutation leads to a disease state.

Ann Graybiel

Ann Graybiel studies the basal ganglia, brain structures that are affected in Parkinson’s and Huntington’s disease as well as many psychiatric disorders. The major hallmark of Parkinson’s disease is the degeneration of dopamine neurons that innervate a part of the basal ganglia known as the striatum. This degeneration results in disordered movement. In some cases, it can also affect mood and cognition. Graybiel’s work spans many levels, from genetics and biochemistry to electrophysiology and behavior. Her overall goal is to understand how the basal ganglia contribute to so many aspects of normal behavior, and how damage to these structures can lead to disease.

Much of Graybiel’s work is focused on basic understanding of basal ganglia function, but she has also made many contributions to understanding the mechanisms of neurodegenerative diseases. In one recent study, for example, her lab examined the brain’s response to L-dopa, a drug widely used to treat Parkinson’s disease. Although L-dopa often improves symptoms of the disease, it can also produce unwanted side effects, such as involuntary movements known as dyskinesias. Graybiel has identified genes that are specifically activated by L-dopa and whose expression is associated with (and may help explain) the appearance of dyskinesias. In another recent study, Graybiel collaborated with a team of clinical neurologists and found differences in the brains of Huntington’s patients that could explain why some but not all patients experience mood disorders in addition to movement disorders.

John Gabrieli

John Gabrieli uses neuroimaging technologies such as MRI to study brain function in health and disease. One of his main interests is human memory, and how it changes over the course of a lifetime. He has studied the different types of memory loss that accompany normal aging and Alzheimer’ disease, and the brain changes that may explain these behavioral effects. One goal of this work is to use neuroimaging to identify those individuals at greatest risk for Alzheimer’s disease, and to predict the progression of the disease from mild cognitive impairment to full-blown Alzheimer’s. Gabrieli has also studied the neurobiological effects of cognitive training, including ‘brain training’ regimes that may help to slow the effects of aging and disease.

Other insights from McGovern Institute research

Important advances in disease research depend heavily on basic scientific discoveries, and on new technologies that were originally developed for basic research. Many researchers at the McGovern Institute are conducting research with direct relevance to disease, often in collaboration with clinical researchers in Boston and elsewhere. Some recent examples are summarized below.

Emilio Bizzi studies the control of movement, and in particular how the brain solves the computational problem of muscle activation. The human body has over 600 muscles, so whenever the brain produces a movement, it is selecting from a vast number of possible combinations of muscle contractions. Bizzi’s work suggests that the brain solves – or at least reduces – this computational problem by activating groups of muscles in specific combinations, known as synergies. He has found that a relatively small number of synergies represent the building blocks from which we produce an infinite variety of complex movements. This basic research on motor control has recently begun to suggest novel approaches to rehabilitation following stroke or brain injury. In collaboration with clinical neurologists in Venice, Italy, Bizzi recently found that these modules are preserved following stroke, but that the patient’s ability to activate them is impaired. His results suggest that it may be possible to develop focused rehabilitation methods that specifically train the impaired synergies. As a first step toward this goal, Bizzi and his collaborators plan to monitor a group of stroke patients as they undergo rehabilitation therapy, to determine whether the post-stroke improvements in motor function can be explained as changes in the activation pattern of specific synergies.

Alan Jasanoff, an expert on MRI imaging technology, has collaborated with colleagues at the Whitehead Institute to study neurodegeneration in a mouse model of prion disease. These diseases, which include Creutzfeld-Jacob disease and ‘mad cow’ disease, involve infective agents known as prions, whose biological effects are still poorly understood. Jasanoff’s work in this area has focused on understanding how prion diseases affect the structure of the brain. The researchers have used MRI to track the progression of the disease process in different brain regions, and to understand how these anatomical changes are related to the observed behavioral deficits.

Martha Constantine-Paton studies the role of neural plasticity in shaping the developing brain. In collaboration with researchers at Massachusetts General Hospital and in Brisbane, Australia, she has studied a mouse genetic model of familial ALS (Lou Gehrig’s disease), and has identified abnormalities in electrical activity that are among the earliest known signs of the disease process. She also recently collaborated with stem cell researchers at Whitehead Institute and McLean Hospital to study the function of transplanted neurons in a rat model of Parkinson’s disease.

Ed Boyden is a pioneer in the development of optogenetic technology, a method that allows brain activity to be controlled by light. This new technology is already providing many new insights into normal brain function and into the mechanisms underlying a variety of brain disorders. For example, Boyden is currently collaborating with computational neuroscientists at Boston University to understand the brain wave activity that is characteristic of Parkinson’s disease. In the longer term, optogenetics may be provide a new form of therapeutic brain stimulation, an alternative to the implanted electrodes that are currently used to treat Parkinson’s and other motor disorders. In collaboration with Robert Desimone, Boyden’s team has recently demonstrated that optogenetics is effective in macaque monkeys, an important step on the path to eventual therapeutic applications.

Selected references

Emilio Bizzi:
Stability of muscle synergies for voluntary actions after cortical stroke in humans. Cheung VC, Piron L, Agostini M, Silvoni S, Turolla A, Bizzi E. Proc Natl Acad Sci U S A. 2009 Oct 30.

Ed Boyden:

Striatum as a possible source of exaggerated beta oscillations in Parkinson’s disease: Insights from computational models. McCarthy MM, Han X, Boyden ES, Kopell N. Soc Neurosci Abstr (2009) 629.26

Millisecond-timescale optical control of neural dynamics in the nonhuman primate brain. Han X, Qian X, Bernstein JG, Zhou HH, Franzesi GT, Stern P, Bronson RT, Graybiel AM, Desimone R, Boyden ES. Neuron.

Martha Constantine-Paton:

Neonatal neuronal circuitry shows hyperexcitable disturbance in a mouse model of the adult-onset neurodegenerative disease amyotrophic lateral sclerosis. van Zundert B, Peuscher MH, Hynynen M, Chen A, Neve RL, Brown RH Jr, Constantine-Paton M, Bellingham MC. J Neurosci. 2008 Oct 22;28(43):10864-74.

Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Wernig M, Zhao JP, Pruszak J, Hedlund E, Fu D, Soldner F, Broccoli V, Constantine-Paton M, Isacson O, Jaenisch R. Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5856-61.
2009 Apr 30;62(2):191-8.

John Gabrieli:
fMRI activation changes during successful episodic memory encoding and recognition in amnestic mild cognitive impairment relative to cognitively healthy older adults. Trivedi MA, Murphy CM, Goetz C, Shah RC, Gabrieli JD, Whitfield-Gabrieli S, Turner DA, Stebbins GT. Dement Geriatr Cogn Disord. 2008;26(2):123-37.

Healthy and pathological processes in adult development: new evidence from neuroimaging of the aging brain. Hedden T, Gabrieli JD. Curr Opin Neurol. 2005 Dec;18(6):740-7.

Ann Graybiel:
Dysregulation of CalDAG-GEFI and CalDAG-GEFII predicts the severity of motor side-effects induced by anti-parkinsonian therapy. Crittenden JR, Cantuti-Castelvetri I, Saka E, Keller-McGandy CE, Hernandez LF, Kett LR, Young AB, Standaert DG, Graybiel AM. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2892-6.

Striosomes and mood dysfunction in Huntington’s disease. Tippett LJ, Waldvogel HJ, Thomas SJ, Hogg VM, van Roon-Mom W, Synek BJ, Graybiel AM, Faull RL. Brain. 2007 Jan;130(Pt 1):206-21.

H Robert Horvitz:
Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr. Science. 2009 Feb 27;323(5918):1205-8.

The C. elegans protein CEH-30 protects male-specific neurons from apoptosis independently of the Bcl-2 homolog CED-9. Schwartz HT, Horvitz HR. Genes Dev. 2007 Dec 1;21(23):3181-94.

Alan Jasanoff:
Context-dependent perturbation of neural systems in transgenic mice expressing a cytosolic prion protein. Faas H, Jackson WS, Borkowski AW, Wang X, Ma J, Lindquist S, Jasanoff A.Neuroimage. 2009 Oct 14.

Spontaneous generation of prion infectivity in fatal familial insomnia knockin mice. Jackson WS, Borkowski AW, Faas H, Steele AD, King OD, Watson N, Jasanoff A, Lindquist S. Neuron. 2009 Aug 27;63(4):438-50.