Research in the Cell Biology Section, Neurogenetics Branch focuses on the molecular mechanisms underlying a number of neurodegenerative disorders, including mitochondrial disorders, dystonia, and the hereditary spastic paraplegias (HSPs). These disorders, which together afflict millions of Americans, worsen insidiously over a number of years, and treatment options are limited for many of them. Our laboratory is investigating inherited forms of these disorders, using molecular and cell biology approaches to study how mutations in disease genes ultimately result in cellular dysfunction. In this project, we are focusing on the HSPs. One major research theme involves the characterization and functional analysis of the hereditary spastic paraplegia type 3A (SPG3A) protein, atlastin-1. In 2009, we reported in the journal Cell that atlastin-1 is a member of a ubiquitous family of GTPases that interact with two families of ER shaping proteins to generate the tubular endoplasmic reticulum (ER) network. Interestingly, atlastin-1 interacts with the SPG31 protein REEP1, which is an ER shaping protein, as well as the SPG4 protein spastin, a microtubule-severing ATPase. In 2010, we published a study in the Journal of Clinical Investigation demonstrating that these three proteins interact with one another to organize the tubular ER network in conjunction with the microtubule cytoskeleton. Since SPG3A, SPG4, and SGP31 account for well over 50% of all HSP cases, we suggest ER network defects as the predominant neuropathologic mechanism for the HSPs. Over the past year, we have continued to develop animal models for SPG31 (knock out) and SPG3A (knockout and knock in) to evaluate the extent of ER morphology changes using both in vivo and ex vivo studies. We are employing both high-throughput electron microscopy (in collaboration with Dr. Mark Terasaki) and super-resolution confocal microscopy to examine the changes in tubular ER within neuronal axons in response to these genetic manipulations. In addition, we have identified interactions of these proteins with several other proteins mutated in the HSPs, expanding the number of HSP cases related to defects in ER network formation. A key aspect of ER function possibly related to disease pathogenesis is the formation of lipid droplets, and this is an area of emphasis for our cellular and organismal studies. Last, we are actively generating in situ models for many of the HSPs through the production of patient-derived, induced pluripotent stem cells that are then differentiated into telecephalic neurons, in collaboration with Dr. Xue-Jun Li. Taken together, we expect that our studies will advance our understanding of the molecular pathogenesis of the HSPs. Such an understanding at the molecular and cellular levels will hopefully lead to novel treatments to prevent the progression of these disorders.

Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2013
Total Cost
$1,021,212
Indirect Cost
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State
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Nixon-Abell, Jonathon; Berwick, Daniel C; Grannó, Simone et al. (2016) Protective LRRK2 R1398H Variant Enhances GTPase and Wnt Signaling Activity. Front Mol Neurosci 9:18
Blackstone, Craig; Belmont, Lisa D (2016) Cell biology and the ""real world"". Mol Biol Cell 27:878-9
Rinaldi, Carlo; Schmidt, Thomas; Situ, Alan J et al. (2015) Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia. JAMA Neurol 72:561-70
Renvoisé, Benoît; Chang, Jaerak; Singh, Rajat et al. (2014) Lysosomal abnormalities in hereditary spastic paraplegia types SPG15 and SPG11. Ann Clin Transl Neurol 1:379-389
Goyal, Uma; Renvoisé, Benoît; Chang, Jaerak et al. (2014) Spastin-interacting protein NA14/SSNA1 functions in cytokinesis and axon development. PLoS One 9:e112428
Zhu, Peng-Peng; Denton, Kyle R; Pierson, Tyler Mark et al. (2014) Pharmacologic rescue of axon growth defects in a human iPSC model of hereditary spastic paraplegia SPG3A. Hum Mol Genet 23:5638-48
Zhao, Guohua; Blackstone, Craig (2014) ER morphology: sculpting with XendoU. Curr Biol 24:R1170-2
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Denton, Kyle R; Lei, Ling; Grenier, Jeremy et al. (2014) Loss of spastin function results in disease-specific axonal defects in human pluripotent stem cell-based models of hereditary spastic paraplegia. Stem Cells 32:414-23
Donkervoort, S; Dastgir, J; Hu, Y et al. (2014) Phenotypic variability of a likely FA2H founder mutation in a family with complicated hereditary spastic paraplegia. Clin Genet 85:393-5

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