Browsing by Author "Banks, Susan M. L."
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- ItemAcute increase of α-synuclein inhibits synaptic vesicle recycling evoked during intense stimulation(Molecular Biology of the Cell (MBoC), 2014-10) Busch, David J.; Oliphint, Paul A.; Walsh, Rylie B.; Banks, Susan M. L.; Woods, Wendy S.; George, Julia M.; Morgan, Jennifer R.Parkinson's disease is associated with multiplication of the α-synuclein gene and abnormal accumulation of the protein. In animal models, α-synuclein overexpression broadly impairs synaptic vesicle trafficking. However, the exact steps of the vesicle trafficking pathway affected by excess α-synuclein and the underlying molecular mechanisms remain unknown. Therefore we acutely increased synuclein levels at a vertebrate synapse and performed a detailed ultrastructural analysis of the effects on presynaptic membranes. At stimulated synapses (20 Hz), excess synuclein caused a loss of synaptic vesicles and an expansion of the plasma membrane, indicating an impairment of vesicle recycling. The N-terminal domain (NTD) of synuclein, which folds into an α-helix, was sufficient to reproduce these effects. In contrast, α-synuclein mutants with a disrupted N-terminal α-helix (T6K and A30P) had little effect under identical conditions. Further supporting this model, another α-synuclein mutant (A53T) with a properly folded NTD phenocopied the synaptic vesicle recycling defects observed with wild type. Interestingly, the vesicle recycling defects were not observed when the stimulation frequency was reduced (5 Hz). Thus excess α-synuclein impairs synaptic vesicle recycling evoked during intense stimulation via a mechanism that requires a properly folded N-terminal α-helix.
- ItemAuxilin is essential for Delta signaling(Company Of Biologists Limited, 2008-03) Eun, Suk Ho; Banks, Susan M. L.; Fischer, Janice A.Endocytosis regulates Notch signaling in both signaling and receiving cells. A puzzling observation is that endocytosis of transmembrane ligand by the signaling cells is required for Notch activation in adjacent receiving cells. A key to understanding why signaling depends on ligand endocytosis lies in identifying and understanding the functions of crucial endocytic proteins. One such protein is Epsin, an endocytic factor first identified in vertebrate cells. Here, we show in Drosophila that Auxilin, an endocytic factor that regulates Clathrin dynamics, is also essential for [...]
- ItemChaperone proteins as ameliorators of α-synuclein-induced synaptic pathologies: Insights into Parkinson's disease(Wolters Kluwer Medknow Publications, 2021-06) Banks, Susan M. L.; Medeiros, Audrey T.; Sousa, Rui; Lafer, Eileen M.; Morgan, Jennifer R.Neurodegenerative disorders, such as Parkinson’s disease (PD) and other synucleinopathies, impact the lives of millions of patients and their caregivers. Synucleinopathies include PD, dementia with Lewy Bodies (DLB), multiple system atrophy, and several Alzheimer’s Disease variants. They are clinically characterized by intracellular inclusions called Lewy Bodies, which are rich in atypical aggregates of the protein α-synuclein. While dopaminergic neurons in the substantia nigra are particularly susceptible to α-synuclein-induced aggregation and neurodegeneration, glutamatergic neurons in other brain regions (e.g. cortex) are also frequently affected in PD and other synucleinopathies (Schulz-Schaeffer 2010). Several point mutations in the α-synuclein gene (SNCA), as well as duplication/triplication of SNCA, are linked to familial Parkinson’s disease.
- ItemDrosophila klaroid encodes a SUN domain protein required for Klarsicht localization to the nuclear envelope and nuclear migration in the eye(Taylor & Francis, 2007-04) Kracklauer, Martin P.; Banks, Susan M. L.; Xie, Xuanhua; Wu, Yaning; Fischer, Janice A.KASH (Klarsicht/Anc-1/Syne homology) domain proteins are cytoskeleton-associated proteins localized uniquely to the outer nuclear membrane. Klarsicht is a KASH protein required for nuclear migration in differentiating cells of the Drosophila eye. The C-terminal KASH domain of Klarsicht resides in the perinuclear space, and the cytoplasmic moiety connects to the microtubule organizing center. In C. elegans and vertebrate cells, SUN (Sad1/UNC-84) domain proteins reside in the inner nuclear membrane and tether KASH proteins to the outer nuclear membrane. Is there a Drosophila SUN protein that performs a similar function, and if so, is it like Klarsicht, obviously essential for [...]
- ItemThe functions of auxilin and Rab11 in Drosophila suggest that the fundamental role of ligand endocytosis in notch signaling cells is not recycling(Public Library of Science, 2011-03-23) Banks, Susan M. L.; Cho, Bomsoo; Eun, Eun; Lee, Ji-Hoon; Windler, Sarah L; Xie, Xuanhua; Bilder, David; Fischer, Janice A.Notch signaling requires ligand internalization by the signal sending cells. Two endocytic proteins, epsin and auxilin, are essential for ligand internalization and signaling. Epsin promotes clathrin-coated vesicle formation, and auxilin uncoats clathrin from newly internalized vesicles. Two hypotheses have been advanced to explain the requirement for ligand endocytosis. [...]
- ItemHsc70 ameliorates the vesicle recycling defects caused by excess α-synuclein at synapses(Society for Neuroscience, 2020-01) Banks, Susan M. L.; Medeiros, Audrey T.; McQuillan, Molly; Busch, David J.; Ibarraran-Viniegra, Ana Sophia; Sousa, Rui; Lafer, Eileen M.; Morgan, Jennifer R.α-Synuclein overexpression and aggregation are linked to Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and several other neurodegenerative disorders. In addition to effects in the cell body, α-synuclein accumulation occurs at presynapses where the protein is normally localized. While it is generally agreed that excess α-synuclein impairs synaptic vesicle trafficking, the underlying mechanisms are unknown. We show here that acute introduction of excess human α-synuclein at a classic vertebrate synapse, the lamprey reticulospinal (RS) synapse, selectively impaired the uncoating of clathrin-coated vesicles (CCVs) during synaptic vesicle recycling, leading to an increase in endocytic intermediates and a severe depletion of synaptic vesicles. Furthermore, human α-synuclein and lamprey +-synuclein both interact in vitro with Hsc70, the chaperone protein that uncoats CCVs at synapses. After introducing excess α-synuclein, Hsc70 availability was reduced at stimulated synapses, suggesting Hsc70 sequestration as a possible mechanism underlying the synaptic vesicle trafficking defects. In support of this hypothesis, increasing the levels of exogenous Hsc70 along with α-synuclein ameliorated the CCV uncoating and vesicle recycling defects. These experiments identify a reduction in Hsc70 availability at synapses, and consequently its function, as the mechanism by which α-synuclein induces synaptic vesicle recycling defects. To our knowledge, this is the first report of a viable chaperone-based strategy for reversing the synaptic vesicle trafficking defects associated with excess α-synuclein, which may be of value for improving synaptic function in PD and other synuclein-linked diseases.
- ItemReducing synuclein accumulation improves neuronal survival after spinal cord injury(Elsevier Inc., 2016-04) Fogerson, Stephanie M.; van Brummen, Alexandra J.; Busch, David J.; Allen, Scott R.; Roychaudhuri, Robin; Banks, Susan M. L.; Klärner, Frank-Gerrit; Schrader, Thomas; Bitan, Gal; Morgan, Jennifer R.Spinal cord injury causes neuronal death, limiting subsequent regeneration and recovery. Thus, there is a need to develop strategies for improving neuronal survival after injury. Relative to our understanding of axon regeneration, comparatively little is known about the mechanisms that promote the survival of damaged neurons. To address this, we took advantage of lamprey giant reticulospinal neurons whose large size permits detailed examination of post-injury molecular responses at the level of individual, identified cells.[...]