July 9, 2007 

The Milton Safenowitz Post-Doctoral Fellowship for ALS Research

Four young investigators are poised to join the effort to find effective therapies for ALS funded by The Milton Safenowitz Post-Doctoral Fellowship for ALS Research. These promising scientists have proposed innovative and important efforts that will accelerate progress in the field. The ALS Association is especially committed to bringing new concepts and methods into ALS research, and young scientists play an important role in this process.

Determining the Contribution of Mitochondrial Dysfunction in ALS Pathogenesis
Sandrine Da Cruz, Ph.D., working with Don Cleveland at the Ludwig Institute at the University of California, San Diego, will study the role in ALS of the mitochondria, the cellular power supplies that fuel all metabolic reactions. Mice are available that have been genetically manipulated to have either enhanced activities of a key enzyme within the mitochondria or to contain more of these cell constituents. Da Cruz will breed each of these mice to two different mice mutants, each having a different change to the protein, copper-zinc superoxide dismutase (SOD1), responsible for some inherited cases of ALS. Resulting mice will have changes in mitochondrial enzymes as well as altered SOD1. These mice should be able to show if enhancing mitochondrial function will aid in the course of the ALS symptoms. Knowing how the mitochondria contribute in ALS will guide therapeutic efforts in the disease. Da Cruz will also see whether mitochondria are compromised primarily in motor neurons or in muscle. For this, she will use mice that have been genetically modified to have enhanced mitochondrial activity either in motor neurons or muscle.

The Metabolome of the Cerebrospinal Fluid: Signature for ALS
Gurudutt Pendyala, Ph.D., working with Howard Fox, M.D., Ph.D., at The Scripps Research Institute, La Jolla, Calif., will seek to find a marker of the disease in the products of metabolism of the human body as well as in animal models for ALS. Changes in the body’s metabolism might be reflected in the small molecules produced by the body’s chemical reactions and present in the fluid that bathes the brain and spinal cord. The search through the so-called metabolome will uncover those metabolic products whose amounts change in response to the disease process in order to identify a panel of molecules that report the presence and progress of the disorder. A reliable and reproducible set of metabolic biomarkers would allow faster diagnosis, streamlined clinical trials, and a window into the changes that could provide therapeutic targets. The Fox lab has an established record of providing biomarkers in the field of HIV dementia and will now apply their expertise to ALS.

Molecular Controls over Early Specification and Differentiation of Corticospinal Neurons (Upper Motor Neurons)Caroline Rouaux, Ph.D., working with Paola Arlotta, Ph.D., Massachusetts General Hospital will build on progress achieved with funding from The ALS Association in projects originating under the direction of Jeffrey Macklis, Ph.D., at Harvard. These investigators have found some of the control signals that guide stem cells in the developing brain to send their long extensions, called axons, down the spinal cord to connect to the lower motor neurons that contract muscles. Rouaux will use genetic engineering to confirm if these signal molecules are directing certain stem cells to become the motor neurons that extend down the spinal cord from the cerebral cortex (cortico-spinal or upper motor neurons) during development. The information should give important insights into stem cell therapy for ALS that could show a way to produce upper motor neurons to replace the dying ones.

Effect of Astrocytic Nrf2 Activation on the Onset and Progression of Motor Neuron Degeneration in an ALS-Animal Model
Marcelo Vargas, Ph.D., working with Jeffrey Johnson, Ph.D., at the University of Wisconsin, Madison, will examine the role of a defense system present in the cells that surround and aid the motor neurons. Astrocytes, star shaped cells that buffer the motor neurons from potentially toxic products of normal cell chemistry, have a defense system headed by a protein abbreviated Nrf2. With mice that make more than the usual amount Nrf2 in astrocytes, Vargas will see if this defense system might be reinforced for ALS by crossing Nrf2 over-expressing mice with those making the mutant SOD1 protein. This experiment should define whether the Nrf2 system is a way to affect the disease process and therefore a promising avenue toward effective therapy.

Please see The ALS Association Active Research Projects Searchable Database to read about currently funded projects throughout the year.