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 emphasizing investigations into the regulation of mitochondrial morphology within cells. Indeed, fusion and fission events that regulate mitochondrial morphology are essential for proper mitochondrial function, and their regulation is increasingly recognized in diverse cellular functions. Mitochondrial fission events in mammals are orchestrated by at least two proteins;the dynamin-related protein Drp1 and the integral membrane protein Fis1. The reciprocal process of mitochondrial fusion also requires large GTPases of the dynamin superfamily: OPA1 and the mitofusins Mfn1 and Mfn2. Since mutations in Drp1, Mfn2, and OPA1 have been identified in patients with inherited neurological disorders, and there is prominent fragmentation of mitochondria during programmed cell death, insights into the regulation of these processes is highly relevant clinically. In 2007, we published a study demonstrating that cAMP-dependent protein phosphorylation of the Drp1 protein modulates its GTPase activity as well as mitochondrial morphology. We now have collaborative investigations underway focusing on the relevance of this modification in the regulation of a number of intracellular processes, including one study that was published in 2008. In addition, we have identified the sites of sumoylation within the Drp1 protein and are currently using dominant-negative approaches to determine the functional role of sumoylation in Drp1 function. We have recently completed a study of the Drp1 A395D mutation that caused a neonatally fatal mitochondrial disorder due to markedly diminished mitochondrial fission. In this study, we were able to show that this mutation resulted in loss of higher-order multimeric interactions of the Drp1 protein. Lastly, in ongoing studies we have identified a number of Drp1-interacting proteins that may be involved in the proper distribution of mitochondria within cells. Together, these studies are continuing to provide critical insights into the regulation of mitochondrial morphology within a cell, an area of increasing clinical relevance and importance.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Zip Code
Blackstone, Craig (2016) KIF1B? and Neuroblastoma: Failure to Divide and Cull. Dev Cell 36:127-8
Dworzak, Jenny; Renvoisé, Benoît; Habchi, Johnny et al. (2015) Neuronal Cx3cr1 Deficiency Protects against Amyloid ?-Induced Neurotoxicity. PLoS One 10:e0127730
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
Blackstone, Craig (2014) Huntington's disease: from disease mechanisms to therapies. Drug Discov Today 19:949-50
Roda, Ricardo H; Schindler, Alice B; Blackstone, Craig et al. (2014) Laing distal myopathy pathologically resembling inclusion body myositis. Ann Clin Transl Neurol 1:1053-8
Anderson, Caroline A; Blackstone, Craig (2013) SUMO wrestling with Drp1 at mitochondria. EMBO J 32:1496-8
Gray, Josie J; Zommer, Amelia E; Bouchard, Ron J et al. (2013) N-terminal cleavage of the mitochondrial fusion GTPase OPA1 occurs via a caspase-independent mechanism in cerebellar granule neurons exposed to oxidative or nitrosative stress. Brain Res 1494:28-43
Pierson, Tyler Mark; Adams, David; Bonn, Florian et al. (2011) Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases. PLoS Genet 7:e1002325
Blackstone, Craig; Chang, Chuang-Rung (2011) Mitochondria unite to survive. Nat Cell Biol 13:521-2
Chang, Chuang-Rung; Blackstone, Craig (2010) Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1. Ann N Y Acad Sci 1201:34-9

Showing the most recent 10 out of 15 publications