10 research outputs found
Superconformal Yang-Mills quantum mechanics and Calogero model with OSp(N|2,R) symmetry
In spacetime dimension two, pure Yang-Mills possesses no physical degrees of
freedom, and consequently it admits a supersymmetric extension to couple to an
arbitrary number, N say, of Majorana-Weyl gauginos. This results in (N,0) super
Yang-Mills. Further, its dimensional reduction to mechanics doubles the number
of supersymmetries, from N to N+N, to include conformal supercharges, and leads
to a superconformal Yang-Mills quantum mechanics with symmetry group
OSp(N|2,R). We comment on its connection to AdS_2 \times S^{N-1} and reduction
to a supersymmetric Calogero model.Comment: 1+28 pages, no figure; Refs added. To appear in JHE
Uncoupling neuronal death and dysfunction in Drosophila models of neurodegenerative disease
Common neurodegenerative proteinopathies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are characterized by the misfolding and aggregation of toxic protein species, including the amyloid beta (Aß) peptide, microtubule-associated protein Tau (Tau), and alpha-synuclein (αSyn) protein. These factors also show toxicity in Drosophila; however, potential limitations of prior studies include poor discrimination between effects on the adult versus developing nervous system and neuronal versus glial cell types. In addition, variable expression paradigms and outcomes hinder systematic comparison of toxicity profiles. Using standardized conditions and medium-throughput assays, we express human Tau, Aß or αSyn selectively in neurons of the adult Drosophila retina and monitor age-dependent changes in both structure and function, based on tissue histology and recordings of the electroretinogram (ERG), respectively. We find that each protein causes a unique profile of neurodegenerative pathology, demonstrating distinct and separable impacts on neuronal death and dysfunction. Strikingly, expression of Tau leads to progressive loss of ERG responses whereas retinal architecture and neuronal numbers are largely preserved. By contrast, Aß induces modest, age-dependent neuronal loss without degrading the retinal ERG. αSyn expression, using a codon-optimized transgene, is characterized by marked retinal vacuolar change, progressive photoreceptor cell death, and delayed-onset but modest ERG changes. Lastly, to address potential mechanisms, we perform transmission electron microscopy (TEM) to reveal potential degenerative changes at the ultrastructural level. Surprisingly, Tau and αSyn each cause prominent but distinct synaptotoxic profiles, including disorganization or enlargement of photoreceptor terminals, respectively. Our findings highlight variable and dynamic properties of neurodegeneration triggered by these disease-relevant proteins in vivo, and suggest that Drosophila may be useful for revealing determinants of neuronal dysfunction that precede cell loss, including synaptic changes, in the adult nervous system
Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity
Cells respond to stimuli by changes in various processes, including signaling pathways and gene
expression. Efforts to identify components of these responses increasingly depend on mRNA
profiling and genetic library screens, yet the functional roles of the genes identified by these assays
often remain enigmatic. By comparing the results of these two assays across various cellular
responses, we found that they are consistently distinct. Moreover, genetic screens tend to identify
response regulators, while mRNA profiling frequently detects metabolic responses. We developed
an integrative approach that bridges the gap between these data using known molecular interactions,
thus highlighting major response pathways. We harnessed this approach to reveal cellular pathways
related to alpha-synuclein, a small lipid-binding protein implicated in several neurodegenerative
disorders including Parkinson disease. For this we screened an established yeast model for alphasynuclein
toxicity to identify genes that when overexpressed alter cellular survival. Application of
our algorithm to these data and data from mRNA profiling provided functional explanations for many
of these genes and revealed novel relations between alpha-synuclein toxicity and basic cellular
pathways.MGH/MIT Morris Udall Center of Excellence in PD Researc