Laxman D. Gangwani , Ph.D.
lgangwani@mcg.edu

One of the long-term goals of our research program is to understand the molecular mechanisms of neuron degeneration in spinal muscular atrophy (SMA). SMA is an autosomal recessive disease of early childhood caused by mutation of the survival motor neurons (SMN1) gene. This disease is characterized by degeneration of the spinal cord motor neurons caused by low levels of full-length SMN protein. The molecular mechanisms of motor neuron degeneration are unknown and no treatment is available for SMA.

The biochemical defects underlying motor neuron degeneration in SMA are unclear. The defects in nuclear accumulation of SMN in cells derived from SMA patients suggest that the presence of SMN in the nucleus may be critical for the survival of motor neurons. ZPR1 is essential for survival and is required for nuclear accumulation of SMN. The interaction of ZPR1 with SMN is disrupted in cells derived from SMA patients.

The severity of SMA may be influenced by the actions of modifier genes. One potential modifier gene is represented by ZPR1, which is down regulated in patients with SMA. The reduced expression of ZPR1 causes progressive loss of the spinal cord motor neurons in mice. Together, these findings suggest that ZPR1 may play a critical role in the normal function of SMN and may contribute to the pathogenesis of SMA. To determine the role of ZPR1 in SMA pathogenesis a detailed understanding of the neuronal functions of ZPR1, the biochemical defects caused by disruption of SMN-ZPR1 complexes and the molecular mechanisms of motor neuron degeneration is required. We employ biochemical, molecular and genetic approaches to investigate the physiological role of ZPR1 and SMN complexes in neurons using neuron-based cell and animal model systems.

The current research program to understand the pathogenesis of SMA consists of the following projects in the laboratory: (I) To determine the molecular mechanisms of motor neuron degeneration in SMA. (II) To determine the cellular and biochemical defects stemming from alterations in the levels of SMN and ZPR1 and (III) To identify and validate therapeutic targets for neuroprotection to develop suitable strategies for the treatment of SMA.

Laboratory rotations for graduate students are available to study cellular and molecular basis of cell growth and development. Several projects are available, including studies of the molecular mechanisms of neuron degeneration, protein-protein interactions, apoptosis and the cell cycle. Genetic approaches, including gene targeting in mice combined with biochemical and molecular approaches will be employed.