C. elegans Worms Help Find Treatments for Neurodegenerative Disorders

Scientists are learning more about Autism, Alzheimer's, ALS, or other neurodegenerative diseases by replicating the pathological processes of such diseases in worms.

Age-associated neurodegenerative diseases, like Alzheimer's, ALS, and Down Syndrome, place a tremendous burden, both financially and emotionally on families, and this burden is only getting greater as people live longer. Researchers have been working to find therapeutic strategies to minimize the burdens brought about by these diseases for a long time. One such strategy has been to use worms, specifically C. elegans, as a pilot system.  This simple model system allows experimental approaches that are difficult to do in mice (or people!), thereby enabling scientists to more readily take an "unbiased" approach that does not require pre-existing assumptions about how a pathological process works. By using worms to understand the pathological process responsible for neurodegenerative diseases, effective therapies can be developed that rely upon the novel insights found as opposed to the current model of creating therapies prior to knowing how the diseases work.

Dr. Chris Link of the University of Colorado is the molecular geneticist that designed the original models for working with C. elegans in order to study disease pathologies. Dr Link explains that "the best ideas are obvious in retrospect" and this concept has been foundational for him as a scientist. As a young scientist, when he first attempted to make invertebrate models, it was difficult to get funding because no one had previously attempted to use this method. However, because of the ultimate success of his experiments, a subfield of over 100 labs around the world are currently using Dr. Link's methods to study neurodegenerative pathology. While specific genes and proteins have been connected to causing heritable forms of diseases, scientists still do not understand how abnormal function or accumulation of these proteins causes neurotoxicity. Through his work with the simple models of C. elegans, Dr. Link tests findings to come closer to developing targeted therapies for a range of diseases.

Dr. Link is currently undertaking 3 specific projects:

  • Mechanisms of beta amyloid toxicity: There is abundant evidence that accumulation of the beta amyloid peptide (the primary component of senile plaques) in the brain initiates the toxic cascade that leads to Alzheimer's disease. Dr. Link is pursuing the hypothesis that some or all of the beta amyloid peptide toxicity results from the ability of this peptide to directly damage membranes. His studies suggest that the response to membrane damage may be an important component of the beta amyloid toxic cascade and that this process might be a target for therapeutic intervention.

  • ALS (Lou Gehrig disease) and the TDP-43 protein: ALS is a progressive, fatal motor disorder caused by death of motor neurons in the spinal cord. Dr. Link is working to better understand the TDP-43 protein which may be responsible for activating immune responses inappropriately therefore leading to motor neuron pathology.

  • Down Syndrome and trisomy of chromosome 21: Down syndrome (DS) is caused by an extra copy of chromosome 21, which results in a range of clinical phenotypes, including intellectual disability, heart defects, high rates of leukemia, and early onset Alzheimer's disease. Until recently it has been difficult to determine to what degree the extra copy of chromosome 21 causes excessive expression of genes on this chromosome.  Using new stem cell technologies, Dr. Link and his team are trying to determine which chromosome 21 genes are overexpressed and which are specifically responsible for DS clinical symptoms. Identification of these genes may allow targeted therapies that might help the over 400,000 people with DS in the United States alone.

Dr. Link's development of the first transgenic invertebrate models for neurodegenerative diseases has therefore given him the most accumulated experience in interpreting these kinds of studies. While many other labs have begun to use this approach, Dr. Link and his team have a long-term perspective that has helped them focus on findings that are transferable to human disease. His work will lead to a compelling case that the pathological processes he has identified are directly related to the diseases he studies and therefore, he will be able to translate this knowledge into therapeutics to help manage, treat, and perhaps one day cure diseases such as Alzheimer's, ALS, and other neurological conditions.

Bio

  • Dr. Link's background is originally in molecular genetics and developmental biology, and his lab initially began using the invertebrate worm Caenorhabditis elegans for classic developmental genetic studies. In 1992, Dr. Link's group initiated a new series of experiments by transgenically engineering C. elegans to express the human beta amyloid peptide, which is centrally involved in the pathogenesis of Alzheimer's disease. In this model, the beta amyloid peptide accumulates intracellularly, forms amyloid, and results in cellular pathology. The goal of his studies is to understand the molecular and cellular basis of this toxicity, and to investigate how these processes might be involved in Alzheimer's disease. Dr. Link takes advantage of experimental tools available in C. elegans, such as forward genetic screens, microarray-based gene expression studies, and dsRNA-based gene inhibition, to help identify specific genes involved in beta amyloid toxicity.

  • Dr. Link is currently expanding his studies to generate additional transgenic models for other neurodegenerative diseases, including Frontotemporal Dementia and ALS. There is increasing evidence that different neurodegenerative diseases may have common underlying mechanisms, which he hopes to address by comparative transgenic modeling in C. elegans.

  • Website: http://www.colorado.edu/neuroscienceprogram/link.html