Principal Investigator: Robert D. Nicholls, D.Phil. Professor of Genetics in Psychiatry Center for Neurobiology and Behavior Department of Psychiatry University of Pennsylvania Philadelphia, PA 19104
robertn@mail.med.upenn.edu

Scientific Abstract: 

In collaborative studies, we recently identified a NIPA1 gene mutation in two families with SPG6, a hereditary spastic paraplegia (HSP). Individuals with SPG6 show progressive lower-extremity spasticity with axonal degeneration affecting the longest axons in the central nervous system (CNS). NIPA1 has 9 predicted transmembrane (TM) domains and we hypothesize functions as a transporter or receptor of an unknown solute/ligand. In unpublished data, we have shown that Nipa1 is a membrane protein that is expressed in specific neurons within cerebral cortex, hippocampus and spinal cord of mouse and human. Using electron microscopy and other techniques, we have also determined the likely subcellular membrane location for NIPA1. As axonal degeneration occurs in HSP, NIPA1 function is required for maintenance of corticospinal axons in adult life and we hypothesize that NIPA1 is required for embryonic neuron and axon development. To test these hypotheses, we propose:

Aim 1

NIPA1 subcellular localization, expression, and modification will be examined using multiple techniques on neuronal cell lines and mouse tissue sections with anti-NIPA1 antibodies and those specific for subcellular organelles or HSP polypeptides. Aim 2. The developmental role of Nipa1 in a loss of function mouse model will be determined, while Aim 3. Transgenic studies of Nipa1 overexpression and SPG6 models will generate mouse models to determine the pathological basis of HSP. The mouse models, with controls, will be analyzed for histological, pathological and neurological/behavioral phenotypes from birth to age 1 year. Given roles of NIPA1 in corticospinal axon maintenance and membrane trafficking, NIPA1 and/or its transported solute/ligand are therapeutic targets for corticospinal axon diseases and injuries.