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 the current project, we have been investigating HSPs that result from defects in proteins implicated in endocytic trafficking. These include the complicated HSP known as Troyer syndrome (SPG20), which is cause by mutations in the spartin gene that likely result in complete loss of the spartin protein. We have recently reported that the spartin protein interacts with the ESCRT-III protein IST1 and is involved in cytokinesis. We are currently investigating the function of spartin in the nervous system by analyzing spartin-null mice that we have generated as a murine model of Troyer syndrome. In a related study, we investigated the complicated HSP known as MAST syndrome (SPG21), which is caused by a large deletion in the gene for the acid cluster protein maspardin. We have generated maspardin-null mice as a murine model for this disorder and are investigating these animals using behavioral techniques in addition to using neurons and other cells derived from these animals for cellular trafficking studies. A study on this topic was published in the journal Neurogenetics in 2010. Over the past year, we have begun to study the interplay of the proteins that are mutated in SPG11 and SPG15. These proteins interact with one another as well as with a new adaptor protein complex -- AP5. We are using siRNA-mediated depletion studies and structural approaches to investigate the functions of these proteins in cells. Lastly, we are investigating the functions of the SPG8 protein strumpellin, which is part of the WASH protein complex implicated in the shaping of endosomes through alterations of the actin cytoskeleton. 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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Blackstone, Craig (2018) Hereditary spastic paraplegia. Handb Clin Neurol 148:633-652
Blackstone, Craig (2018) Converging cellular themes for the hereditary spastic paraplegias. Curr Opin Neurobiol 51:139-146
Denton, Kyle; Mou, Yongchao; Xu, Chong-Chong et al. (2018) Impaired mitochondrial dynamics underlie axonal defects in hereditary spastic paraplegias. Hum Mol Genet 27:2517-2530
Roda, Ricardo H; Schindler, Alice B; Blackstone, Craig (2017) SCA8 should not be tested in isolation for ataxia. Neurol Genet 3:e150
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Hirst, Jennifer; Madeo, Marianna; Smets, Katrien et al. (2016) Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48). Neurol Genet 2:e98
Roda, Ricardo H; FitzGibbon, Edmond J; Boucekkine, Houda et al. (2016) Neurologic syndrome associated with homozygous mutation at MAG sialic acid binding site. Ann Clin Transl Neurol 3:650-4
Fraidakis, Matthew J; Brunetti, Maura; Blackstone, Craig et al. (2016) Novel Compound Heterozygous Spatacsin Mutations in a Greek Kindred with Hereditary Spastic Paraplegia SPG11 and Dementia. Neurodegener Dis 16:373-81
Lee, Seongju; Chang, Jaerak; Blackstone, Craig (2016) FAM21 directs SNX27-retromer cargoes to the plasma membrane by preventing transport to the Golgi apparatus. Nat Commun 7:10939
Hirst, Jennifer; Edgar, James R; Esteves, Typhaine et al. (2015) Loss of AP-5 results in accumulation of aberrant endolysosomes: defining a new type of lysosomal storage disease. Hum Mol Genet 24:4984-96

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