Understanding neurodegeneration

Scientists from the Salk Institute have made a discovery that has profound implications for the understanding of a fatal human genetic disorder. As published in Genes & Development, Dr. Carolee Barlow and colleagues have determined that the gene ATM is essential for the normal differentiation, development and survival of adult neurons.

Ataxia telegiectasia (A-T) is an autosomal recessive disease characterized by progressive neurologic degeneration, immunodeficiency, growth retardation, incomplete sexual maturation, endocrine abnormalities and a predisposition to cancer. This progressive and fatal disease strikes 1 in every 40,000 to 100,000 people in the US and Britain each year. The gene mutated in A-T is ATM. It is known that ATM functions DNA repair and regulation of the cell division cycle in response to ionizing radiation. However, the role of ATM in the nervous system, and how its loss can result in progressive neurodegeneration has remained unclear.

Dr. Barlow and colleagues utilized a new technique to determine how ATM loss results in neurodegeneration. It was recently found that the adult hippocampus region of the brain generates neural progenitor cells in a physiological-stimuli dependent manner. These neural progenitor cells differentiate into all central nervous system cell types. Stimulus, like voluntary exercise, increases the rate of neurogenesis and survival of neural cells. In order to elucidate the role of ATM in neural development, Dr. Barlow and colleagues compared the rates of neural progenitor cell proliferation, differentiation and neuronal survival in normal mice and ATM mutant mice.

The research team found that ATM mutant neural progenitor cells have a higher basal proliferation rate associated with genomic instability. Post exercise, ATM mutant progenitor cells showed a marked decrease in proliferation and neuronal differentiation. In addition, the ATM mutant cells that did differentiate into neurons displayed reduced viability. This in vivo work was further supported by related in vitro data. Dr. Barlow and colleagues have thus concluded that ATM is required for neural fate determination and neuronal survival in the adult mammalian brain. This work represents the first steps towards the delineation of a mechanism for neuronal cell loss in progressive neurodegenerative diseases.