Hereditary spastic paraplegia (HSP) is a group of untreatable neurodegenerative disorders with axonal degeneration that causes severe disability. Disturbances in several distinct biochemical pathways, such as abnormalities in cytoskeletal assembly, defects in oxidative phosphorylation and disruption of axonal transport, may lead to a stereotypical phenotype. However, the functions of most HSP genes remain unknown. Many HSP genes are highly conserved, with homologs having been identified in several invertebrate species, such as C. elegans;this suggests important biological roles and provides opportunities to characterize their functions in animal models. Mutations in the novel gene NIPA1 cause a severe form of HSP. We have characterized the intracellular distribution of this protein and showed its transient colocalization with the Golgi system and vesicles that are actively transported to axons in neurons. The mutated protein forms aggregates in the endoplasmic reticulum (ER) and the majority of cells undergo apoptotic cell death. We have also generated C. elegans transgenic animals overexpressing mutated forms of the NIPA1 homolog, which are shown to develop progressive and severe motor paralysis. Similar to mammalian neurons, C. elegans neurons also undergo neuronal death. These results suggest a gain-of-function mechanism of NIPA1 HSP mutations. We have also determined that NIPA1 and atlastin-1 (another gene commonly causing HSP) interact, and HSP atlastin-1 mutations exhibit a negative-dominant effect on endogeneous NIPA1 protein. We propose to further characterize the mechanisms of neuronal degeneration associated with NIPA1 mutations by determining the cellular and molecular consequences of NIPA1 mutations, and the consequences of knock-down expression of NIPA both in neuronal cell cultures and using the C. elegans animal model. We will also explore the mechanisms of atlastin-1 and NIPA1 interactions and changes induced by HSP mutations. Establishing in vitro vertebrate neuronal models and a C. elegans animal model of NIPA1- and atlastin-1- associated HSP will advance our knowledge of the pathogenesis of HSPs caused by these two genes and their interacting proteins. This will allow us to start designing new rational therapeutic approaches based on molecular pathogenesis.
Narrative: Hereditary Spastic Paraplegia (HSP) is a severe untreatable neurological condition causing a progressive disablity. Our proposal will address the molecular pathogenesis of HSP and results of these studies will allow us to start designing new therapies.
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