Research in the Cellular Neurology Unit 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 developed 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 electron microscopy 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 a protein mutated in another form of autosomal dominant HSP, expanding the number of HSP cases related to defects in ER network formation. 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.

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Guinto, Cheick O; Diarra, Salimata; Diallo, Salimata et al. (2017) A novel mutation in KIF5A in a Malian family with spastic paraplegia and sensory loss. Ann Clin Transl Neurol 4:272-275
Roda, Ricardo H; Schindler, Alice B; Blackstone, Craig (2017) De novo REEP2 missense mutation in pure hereditary spastic paraplegia. Ann Clin Transl Neurol 4:347-350
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Zhao, Guohua; Zhu, Peng-Peng; Renvoisé, Benoît et al. (2016) Mammalian knock out cells reveal prominent roles for atlastin GTPases in ER network morphology. Exp Cell Res 349:32-44
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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
Roda, Ricardo H; Rinaldi, Carlo; Singh, Rajat et al. (2014) Ataxia with oculomotor apraxia type 2 fibroblasts exhibit increased susceptibility to oxidative DNA damage. J Clin Neurosci 21:1627-31

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