Morgan
Jennifer R.
Morgan
Jennifer R.
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ArticleHsc70 ameliorates the vesicle recycling defects caused by excess alpha-synuclein at synapses(Society for Neuroscience, 2020-01-15) Banks, Susan M. L. ; Medeiros, Audrey T. ; McQuillan, Molly ; Busch, David J. ; Ibarraran-Viniegra, Ana Sofia ; 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 γ-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.
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ArticleAcute increase of α-synuclein inhibits synaptic vesicle recycling evoked during intense stimulation(American Society for Cell Biology, 2014-10-01) 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.
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ArticleChaperone proteins as ameliorators of alpha-synuclein-induced synaptic pathologies: Insights into Parkinson's disease(Medknow Publications, 2020-11-27) Banks, Susan M. L. ; Medeiros, Audrey T. ; Sousa, Rui ; Lafer, Eileen M. ; Morgan, Jennifer R.α-Synuclein accumulation causes synaptic vesicle trafficking defects and may underlie neurodegenerative disorders: 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. In animal models, these genetic alterations lead to overexpression and aberrant accumulation of α-synuclein within neurons, and eventually to neurodegeneration. Interestingly, in both animal models and human patients, α-synuclein aggregation often occurs at neuronal synapses and within axons prior to the appearance of larger aggregates (i.e. Lewy bodies) and other signs of neurodegeneration (Schulz-Schaeffer 2010; Volpicelli-Daley et al., 2011). The level of synaptic aggregation of α-synuclein is highly correlated with greater cognitive deficits in PD and DLB patients (Schulz-Schaeffer 2010). Thus, it is essential to understand how excess α-synuclein impacts synapses, as this may represent an early stage in the neurodegenerative disease progression and thus a viable target for therapeutic intervention, particularly with respect to cognitive impairment.