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The Journal of Neuroscience, December 17, 2008, 28(51):13938-13951; doi:10.1523/JNEUROSCI.4668-08.2008

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Neurobiology of Disease
Hereditary Spastic Paraplegia-Associated Mutations in the NIPA1 Gene and Its Caenorhabditis elegans Homolog Trigger Neural Degeneration In Vitro and In Vivo through a Gain-of-Function Mechanism

Jiali Zhao,^1 * Dawn S. Matthies,^2 * Emmanuel J. Botzolakis,³ Robert L. Macdonald,^1,2,4 Randy D. Blakely,^2,4,5 and Peter Hedera^1,4,6

Departments of ¹Neurology and ²Pharmacology, ³Program in Neuroscience, ⁴Center for Molecular Neuroscience, ⁵Department of Psychiatry, and ⁶Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee 37232-8552

Correspondence should be addressed to Peter Hedera, Department of Neurology, Vanderbilt University, 465 21st Avenue South, 6140 MRB III, Nashville, TN 37232-8552. Email: peter.hedera{at}vanderbilt.edu

We studied the consequences of expression of wild-type (WT) human NIPA1 and two mutant forms of NIPA1 with known HSP-associated mutations (T45R and G106R) on cultured rat cortical neurons and using equivalent substitutions in the Caenorhabditis elegans NIPA1 homolog CeNIPA. WT NIPA1 localized in transfected neuronal and non-neuronal cells to the Golgi complex, a subset of synaptic vesicles, to a subset of early endosomes, and plasma cell membrane. Mutant NIPA1 accumulated in the endoplasmic reticulum (ER) triggering ER stress and features of apoptotic cell death. Flow cytometric analysis of NIPA1 surface expression demonstrated relatively intact trafficking of mutant forms and only the T45R mutant exhibited modestly reduced patterns of surface expression without evidence for a dominant-negative effect. In vivo pan-neuronal expression of the WT C. elegans NIPA1 homolog (CeNIPA) was well tolerated, with no obvious impact on neuronal morphology or behavior. In striking contrast, expression of CeNIPA bearing HSP-associated mutations caused a progressive neural degeneration and a clear motor phenotype. Neuronal loss in these animals began at day 7 and by day 9 animals were completely paralyzed. These effects appeared to arise from activation of the apoptotic program triggered by unfolded protein response (UPR), as we observed marked modifications of motor and cellular phenotype when mutant NIPA1 was expressed in caspase (ced-3)- and UPR (xbp-1)-deficient backgrounds. We propose that HSP-associated mutations in NIPA1 lead to cellular and functional deficits through a gain-of-function mechanism supporting the ER accumulation of toxic NIPA1 proteins.

Key words: hereditary spastic paraplegia; NIPA1; Caenorhabditis elegans; flow cytometry; animal model; unfolded protein response

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Received Sept. 29, 2008; revised Nov. 3, 2008; accepted Nov. 10, 2008.

Correspondence should be addressed to Peter Hedera, Department of Neurology, Vanderbilt University, 465 21st Avenue South, 6140 MRB III, Nashville, TN 37232-8552. Email: peter.hedera{at}vanderbilt.edu

This article has been cited by other articles:

				H. T.H. Tsang, T. L. Edwards, X. Wang, J. W. Connell, R. J. Davies, H. J. Durrington, C. J. O'Kane, J. P. Luzio, and E. Reid The hereditary spastic paraplegia proteins NIPA1, spastin and spartin are inhibitors of mammalian BMP signalling Hum. Mol. Genet., October 15, 2009; 18(20): 3805 - 3821. [Abstract] [Full Text] [PDF]

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