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1. Spreading of α-synuclein in the face of axonal transport deficits in Parkinson's disease: A speculative synthesis

Author

Jennifer T. Lamberts, Erin N. Hildebrandt, and Patrik Brundin

Subjects
Braak staging, Prion-like, Mitochondria, Microglia, Oligodendrocytes, Alphaherpesvirus, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Parkinson's disease (PD) is mainly attributed to degeneration of dopamine neurons in the substantia nigra, but its etiopathogenesis also includes impaired protein clearance and axonal transport dysfunction, among others. The spread of α-synuclein (α-syn) aggregates from one neuron to another, in a prion-like manner, is hypothesized to contribute to PD progression. Axonal transport is likely to play a crucial role in this movement of α-syn aggregates between brain regions. At the same time, deficits in axonal transport are suggested to contribute to neuronal failure in PD. In this review, we discuss the apparent contradiction that axonal transport might be essential for disease progression, while dysfunction of axonal transport could simultaneously be a cornerstone of PD pathogenesis. We speculate around models that reconcile how axonal transport can play such a paradoxical role.

Published
2015
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2. Expanding the diversity of mycobacteriophages: insights into genome architecture and evolution.

Author

Welkin H Pope, Deborah Jacobs-Sera, Daniel A Russell, Craig L Peebles, Zein Al-Atrache, Turi A Alcoser, Lisa M Alexander, Matthew B Alfano, Samantha T Alford, Nichols E Amy, Marie D Anderson, Alexander G Anderson, Andrew A S Ang, Manuel Ares, Amanda J Barber, Lucia P Barker, Jonathan M Barrett, William D Barshop, Cynthia M Bauerle, Ian M Bayles, Katherine L Belfield, Aaron A Best, Agustin Borjon, Charles A Bowman, Christine A Boyer, Kevin W Bradley, Victoria A Bradley, Lauren N Broadway, Keshav Budwal, Kayla N Busby, Ian W Campbell, Anne M Campbell, Alyssa Carey, Steven M Caruso, Rebekah D Chew, Chelsea L Cockburn, Lianne B Cohen, Jeffrey M Corajod, Steven G Cresawn, Kimberly R Davis, Lisa Deng, Dee R Denver, Breyon R Dixon, Sahrish Ekram, Sarah C R Elgin, Angela E Engelsen, Belle E V English, Marcella L Erb, Crystal Estrada, Laura Z Filliger, Ann M Findley, Lauren Forbes, Mark H Forsyth, Tyler M Fox, Melissa J Fritz, Roberto Garcia, Zindzi D George, Anne E Georges, Christopher R Gissendanner, Shannon Goff, Rebecca Goldstein, Kobie C Gordon, Russell D Green, Stephanie L Guerra, Krysta R Guiney-Olsen, Bridget G Guiza, Leila Haghighat, Garrett V Hagopian, Catherine J Harmon, Jeremy S Harmson, Grant A Hartzog, Samuel E Harvey, Siping He, Kevin J He, Kaitlin E Healy, Ellen R Higinbotham, Erin N Hildebrandt, Jason H Ho, Gina M Hogan, Victoria G Hohenstein, Nathan A Holz, Vincent J Huang, Ericka L Hufford, Peter M Hynes, Arrykka S Jackson, Erica C Jansen, Jonathan Jarvik, Paul G Jasinto, Tuajuanda C Jordan, Tomas Kasza, Murray A Katelyn, Jessica S Kelsey, Larisa A Kerrigan, Daryl Khaw, Junghee Kim, Justin Z Knutter, Ching-Chung Ko, Gail V Larkin, Jennifer R Laroche, Asma Latif, Kohana D Leuba, Sequoia I Leuba, Lynn O Lewis, Kathryn E Loesser-Casey, Courtney A Long, A Javier Lopez, Nicholas Lowery, Tina Q Lu, Victor Mac, Isaac R Masters, Jazmyn J McCloud, Molly J McDonough, Andrew J Medenbach, Anjali Menon, Rachel Miller, Brandon K Morgan, Patrick C Ng, Elvis Nguyen, Katrina T Nguyen, Emilie T Nguyen, Kaylee M Nicholson, Lindsay A Parnell, Caitlin E Peirce, Allison M Perz, Luke J Peterson, Rachel E Pferdehirt, Seegren V Philip, Kit Pogliano, Joe Pogliano, Tamsen Polley, Erica J Puopolo, Hannah S Rabinowitz, Michael J Resiss, Corwin N Rhyan, Yetta M Robinson, Lauren L Rodriguez, Andrew C Rose, Jeffrey D Rubin, Jessica A Ruby, Margaret S Saha, James W Sandoz, Judith Savitskaya, Dale J Schipper, Christine E Schnitzler, Amanda R Schott, J Bradley Segal, Christopher D Shaffer, Kathryn E Sheldon, Erica M Shepard, Jonathan W Shepardson, Madav K Shroff, Jessica M Simmons, Erika F Simms, Brandy M Simpson, Kathryn M Sinclair, Robert L Sjoholm, Ingrid J Slette, Blaire C Spaulding, Clark L Straub, Joseph Stukey, Trevor Sughrue, Tin-Yun Tang, Lyons M Tatyana, Stephen B Taylor, Barbara J Taylor, Louise M Temple, Jasper V Thompson, Michael P Tokarz, Stephanie E Trapani, Alexander P Troum, Jonathan Tsay, Anthony T Tubbs, Jillian M Walton, Danielle H Wang, Hannah Wang, John R Warner, Emilie G Weisser, Samantha C Wendler, Kathleen A Weston-Hafer, Hilary M Whelan, Kurt E Williamson, Angelica N Willis, Hannah S Wirtshafter, Theresa W Wong, Phillip Wu, Yun jeong Yang, Brandon C Yee, David A Zaidins, Bo Zhang, Melina Y Zúniga, Roger W Hendrix, and Graham F Hatfull

Subjects
Medicine, Science
Abstract

Mycobacteriophages are viruses that infect mycobacterial hosts such as Mycobacterium smegmatis and Mycobacterium tuberculosis. All mycobacteriophages characterized to date are dsDNA tailed phages, and have either siphoviral or myoviral morphotypes. However, their genetic diversity is considerable, and although sixty-two genomes have been sequenced and comparatively analyzed, these likely represent only a small portion of the diversity of the mycobacteriophage population at large. Here we report the isolation, sequencing and comparative genomic analysis of 18 new mycobacteriophages isolated from geographically distinct locations within the United States. Although no clear correlation between location and genome type can be discerned, these genomes expand our knowledge of mycobacteriophage diversity and enhance our understanding of the roles of mobile elements in viral evolution. Expansion of the number of mycobacteriophages grouped within Cluster A provides insights into the basis of immune specificity in these temperate phages, and we also describe a novel example of apparent immunity theft. The isolation and genomic analysis of bacteriophages by freshman college students provides an example of an authentic research experience for novice scientists.

Published
2011
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3. Mitochondrial pyruvate carrier regulates autophagy, inflammation, and neurodegeneration in experimental models of Parkinson’s disease

Author

Trevor A. Tyson, Patrik Brundin, Jerry R. Colca, Jennifer A. Steiner, Erin N. Hildebrandt, Sonia George, Jeffrey H. Kordower, Emily Schulz, Martha L. Escobar Galvis, Zachary Madaj, Jeremy M. Van Raamsdonk, William G. McDonald, Emily Machiela, and Anamitra Ghosh

Subjects
Male, 0301 basic medicine, 1-Methyl-4-phenylpyridinium, Heterozygote, Pyridines, Dopamine, Nigrostriatal pathway, Biology, Neuroprotection, Mice, 03 medical and health sciences, chemistry.chemical_compound, Oxygen Consumption, 0302 clinical medicine, Pyruvic Acid, Autophagy, medicine, Animals, Humans, Caenorhabditis elegans, PI3K/AKT/mTOR pathway, Neuroinflammation, Inflammation, Neurons, Behavior, Animal, Dopaminergic Neurons, MPTP, Neurodegeneration, Dopaminergic, Brain, Neurodegenerative Diseases, Parkinson Disease, General Medicine, medicine.disease, Mitochondria, Cell biology, Mice, Inbred C57BL, Substantia Nigra, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, nervous system, chemistry, Immunology, alpha-Synuclein, Thiazolidinediones, Cell activation, 030217 neurology & neurosurgery, Signal Transduction
Abstract

Mitochondrial and autophagic dysfunction as well as neuroinflammation are involved in the pathophysiology of Parkinson's disease (PD). We hypothesized that targeting the mitochondrial pyruvate carrier (MPC), a key controller of cellular metabolism that influences mTOR (mammalian target of rapamycin) activation, might attenuate neurodegeneration of nigral dopaminergic neurons in animal models of PD. To test this, we used MSDC-0160, a compound that specifically targets MPC, to reduce its activity. MSDC-0160 protected against 1-methyl-4-phenylpyridinium (MPP+) insult in murine and cultured human midbrain dopamine neurons and in an α-synuclein-based Caenorhabditis elegans model. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, MSDC-0160 improved locomotor behavior, increased survival of nigral dopaminergic neurons, boosted striatal dopamine levels, and reduced neuroinflammation. Long-term targeting of MPC preserved motor function, rescued the nigrostriatal pathway, and reduced neuroinflammation in the slowly progressive Engrailed1 (En1+/-) genetic mouse model of PD. Targeting MPC in multiple models resulted in modulation of mitochondrial function and mTOR signaling, with normalization of autophagy and a reduction in glial cell activation. Our work demonstrates that changes in metabolic signaling resulting from targeting MPC were neuroprotective and anti-inflammatory in several PD models, suggesting that MPC may be a useful therapeutic target in PD.

Published
2016
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4. Expanding the diversity of mycobacteriophages: insights into genome architecture and evolution

Author

Chris R. Gissendanner, Jasper Van Kirk Thompson, Cynthia M. Bauerle, Kobie C. Gordon, Stephanie E. Trapani, Sarah C. R. Elgin, Ching-Chung Ko, Asma Latif, Caitlin E. Peirce, Jeremy S. Harmson, Elvis Nguyen, Jillian M. Walton, Siping He, Lauren L. Rodriguez, Jazmyn J. McCloud, Catherine J. Harmon, Angelica N. Willis, Melissa J. Fritz, Jessica A. Ruby, Michael P. Tokarz, Lisa Deng, Samantha T. Alford, Kathryn M. Sinclair, Victoria G. Hohenstein, Lauren Forbes, Erika F. Simms, Jessica M. Simmons, David A. Zaidins, Anthony T. Tubbs, Tyler M. Fox, Erica J. Puopolo, Garrett V. Hagopian, Hilary M. Whelan, Tina Q. Lu, Rachel Miller, Brandy M. Simpson, Emilie G. Weisser, Theresa W. Wong, Luke J. Peterson, Andrew C. Rose, Chelsea L. Cockburn, Tuajuanda C. Jordan, Daniel A. Russell, Yetta M. Robinson, Justin Z. Knutter, Tin-Yun Tang, Daryl Khaw, Ian Winsten Campbell, Stephen B. Taylor, Arrykka S. Jackson, Zein Al-Atrache, Amanda R. Schott, Samantha C. Wendler, John R. Warner, Sequoia I. Leuba, Steven G. Cresawn, J. Bradley Segal, Hannah S. Wirtshafter, Margaret S. Saha, Christine A. Boyer, Melina Y. Zúniga, Lucia P. Barker, Tamsen Polley, Marcella L. Erb, Anjali Menon, Victoria A. Bradley, Amanda J. Barber, Charles A. Bowman, Kaitlin E. Healy, Molly J. McDonough, Kaylee M. Nicholson, A. Javier Lopez, Andrew A. S. Ang, Erica M. Shepard, Leila Haghighat, Matthew B. Alfano, Manuel Ares, Kathryn Sheldon, Murray A. Katelyn, Alexander G. Anderson, Jeffrey D. Rubin, Larisa A. Kerrigan, Lisa Alexander, Krysta R. Guiney-Olsen, Deborah Jacobs-Sera, Junghee Kim, Rebecca Goldstein, Clark L. Straub, Lianne B. Cohen, Anne Georges, Erin N. Hildebrandt, Angela E. Engelsen, Bridget G. Guiza, Russell D. Green, Paul G. Jasinto, Allison M. Perz, Turi A. Alcoser, Laura Z. Filliger, H. S. Rabinowitz, Christopher D. Shaffer, Kathleen Weston-Hafer, William D. Barshop, Blaire C. Spaulding, Andrew J. Medenbach, Joseph Stukey, Michael J. Resiss, Samuel E. Harvey, Aaron A. Best, Nichols E. Amy, Kevin J. He, Erica C. Jansen, Danielle H. Wang, Katrina Nguyen, Katherine Belfield, Christine E. Schnitzler, Seegren V. Philip, Ian M. Bayles, Belle E. V. English, Graham F. Hatfull, Victor Mac, Barbara J. Taylor, Kathryn E. Loesser-Casey, Ingrid J. Slette, Nathan A. Holz, Rachel E. Pferdehirt, Emilie T. Nguyen, Nicholas Lowery, Agustin Borjon, Bo Zhang, Gail V. Larkin, Lynn O. Lewis, Ellen R. Higinbotham, Kevin W. Bradley, Patrick Ng, Brandon C. Yee, Kurt E. Williamson, Anne M. Campbell, Welkin H. Pope, Roger W. Hendrix, Craig L. Peebles, Jonathan M. Barrett, Brandon K. Morgan, Ericka L. Hufford, Ann M. Findley, Kayla N. Busby, Jonathan W. Shepardson, Breyon R. Dixon, Joe Pogliano, Stephanie Guerra, Robert Sjoholm, Dale J. Schipper, Phillip Wu, Steven M. Caruso, Larissa K. Temple, Yun jeong Yang, Jason H. Ho, Kohana D. Leuba, Judith Savitskaya, Alyssa Carey, Peter M. Hynes, Jonathan W. Jarvik, Jonathan Tsay, Corwin N. Rhyan, Marie D. Anderson, Lyons M. Tatyana, Rebekah D. Chew, Jennifer R. Laroche, Jessica S. Kelsey, Jeffrey Corajod, Keshav Budwal, James Sandoz, Tomas Kasza, Alexander P. Troum, Lindsay A. Parnell, Crystal Estrada, Sahrish Ekram, Shannon Goff, Hannah Wang, Mark H. Forsyth, Lauren N. Broadway, Madav K. Shroff, Zindzi D. George, Dee R. Denver, Grant A. Hartzog, Kimberly R. Davis, Kit Pogliano, Isaac R. Masters, Trevor Sughrue, Courtney A. Long, Vincent J. Huang, Gina M. Hogan, and Roberto Puertas Garcia

Subjects
Genome evolution, Science Policy, Mycobacteriophage, Population, lcsh:Medicine, Genome, Viral, Biology, Microbiology, Genome, 03 medical and health sciences, Virology, education, lcsh:Science, Genome Evolution, 030304 developmental biology, Genetics, Comparative genomics, 0303 health sciences, education.field_of_study, Multidisciplinary, Base Sequence, Geography, Mycobacteriophages, 030306 microbiology, lcsh:R, Genetic Variation, Sequence Analysis, DNA, Genomics, Comparative Genomics, Biological Evolution, United States, 3. Good health, Science Education, Evolutionary biology, Viral evolution, DNA, Viral, lcsh:Q, Mobile genetic elements, Research Article
Abstract

Mycobacteriophages are viruses that infect mycobacterial hosts such as Mycobacterium smegmatis and Mycobacterium tuberculosis. All mycobacteriophages characterized to date are dsDNA tailed phages, and have either siphoviral or myoviral morphotypes. However, their genetic diversity is considerable, and although sixty-two genomes have been sequenced and comparatively analyzed, these likely represent only a small portion of the diversity of the mycobacteriophage population at large. Here we report the isolation, sequencing and comparative genomic analysis of 18 new mycobacteriophages isolated from geographically distinct locations within the United States. Although no clear correlation between location and genome type can be discerned, these genomes expand our knowledge of mycobacteriophage diversity and enhance our understanding of the roles of mobile elements in viral evolution. Expansion of the number of mycobacteriophages grouped within Cluster A provides insights into the basis of immune specificity in these temperate phages, and we also describe a novel example of apparent immunity theft. The isolation and genomic analysis of bacteriophages by freshman college students provides an example of an authentic research experience for novice scientists.

Published
2011

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