Power Failure

Since 1999, researchers at Weill Cornell Medicine have been exploring why this apparently seamless process sometimes goes awry, causing motor neurons — the muscle controlling nerve cells — to begin withering away, resulting in conditions such as amyotrophic lateral sclerosis (ALS). A team led by Dr. Giovanni Manfredi, professor of neuroscience in the Feil Family Brain and Mind Research Institute, has pioneered research illuminating how impaired mitochondria play a pivotal role in the development of ALS, the rapidly progressive and fatal neurodegenerative affliction commonly known as Lou Gehrig's disease. "Mitochondria are terribly important for the understanding of neurological disorders, being the final common pathway in which many of these diseases — Alzheimer's, Parkinson's, ALS and others — converge," says the institute's director Dr. Costantino Iadecola, the Anne Parrish Titzell Professor of Neurology. "Even stroke and trauma converge in mitochondria as a major mechanism of disease."

By better understanding the molecular mechanisms underlying mitochondrial changes, Dr. Manfredi and his colleagues hope to spur the development of targeted therapeutics for neurodegenerative conditions. For instance, researchers already know that abnormal protein deposits accumulate in the motor neurons of many people with ALS. Normal protein molecules are folded nearly flawlessly in a three-dimensional configuration. If disruption occurs, proteins can form aggregates — clumps in the cells. Using mouse models, Dr. Manfredi's lab demonstrated that aggregates of misfolded proteins manifest within the mitochondria of the mutant enzyme SOD1, resulting in one of the most common causes of inherited ALS. His laboratory also pioneered work highlighting how faulty calcium regulation in mitochondria and secretion of toxic molecules by supportive cells in the brain, known as astrocytes, result in the death of motor neurons.

Because many neurological conditions involve mitochondrial dysfunction, symptoms can overlap and appear similar, even if the diseases are distinctly different. For instance, some genetic forms of ALS may occur in families with a prevalence of dementia. Contrary to the frequent misperception that the mind remains fully intact in people with ALS, cognitive dysfunction often ensues after paralysis and interferes with memory and behavior. It's also common for dementia to develop in people with Parkinson's disease. "The same person can have both diseases," says Dr. Manfredi, who directs the graduate program in neuroscience, "or different individuals in the same family may have one or the other."

By interfering with the disease pathways that damage mitochondria, Dr. Manfredi aims to stabilize these cellular powerhouses against stress and halt further damage. His team has begun searching for approaches to unravel the mystery surrounding the causes of sporadic ALS, which arises without any known genetic link or family history, and accounts for about 80 percent of all cases. "Sporadic ALS is probably a combination of diseases," he says, with paralysis being the main unifying symptom. His research focuses on genetically altering proteins in human cells and mice — work that could pave the way for promising drugs.

— Susan Kreimer

This story first appeared in Weill Cornell Medicine, Vol. 14, No. 2.