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. A detailed characterization of this mouse was published in the journal Human Molecular Genetics in 2012. 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.

Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2012
Total Cost
$1,351,131
Indirect Cost
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Hirst, Jennifer; Madeo, Marianna; Smets, Katrien et al. (2016) Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48). Neurol Genet 2:e98
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
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
(2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
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
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
Chang, Jaerak; Lee, Seongju; Blackstone, Craig (2014) Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation. J Clin Invest 124:5249-62
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
Blackstone, Craig (2014) Huntington's disease: from disease mechanisms to therapies. Drug Discov Today 19:949-50

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