Understanding the Biophysics of Parkinson’s Disease: Modeling Interactions Between α-Synuclein and Cellular Membranes
The research group of Assistant Professor Jonathan Sachs (Biomedical Engineering) uses MSI for their study of the behavior of proteins and membranes. Mutations in one particularly interesting and important protein, α‐Synuclein (αS), are associated with Parkinson’s disease (PD), a common neurodegenerative disorder that affects 1% of Americans over the age of 65. The pathology of PD involves the selective loss of dopaminergic neurons and the presence of dense, spherical cytoplasmic inclusions, known as Lewy bodies, in the substantia nigra. αS is a 140 amino acid, natively unfolded protein that is the primary component of the fibrillar aggregates that make up Lewy bodies. The precise role of αS in the pathology of PD remains unclear. However, findings in early-onset PD patients, namely the identification of three rare autosomal dominant mutations, along with incidences of multiplication of the αS gene, have established that αS is critical to the progression of the disease.
In its normal state, αS is abundantly expressed in neurons, where some of it is localized to the pres-synaptic nerve endings and binds tightly to synaptic vesicles. The native function of αS is poorly understood, although some evidence suggests that it may play a role both in maintaining neuronal plasticity and in the regulation of synaptic vesicle recycling. It has also been proposed that interactions of specific aggregated states of αS with cellular membranes may be a mechanism of cytotoxicity in PD. Because both its normal function as a synaptic vesicle-associated protein, as well as its proposed pathological function in PD, likely involve interactions with cellular membranes, a complete characterization of the nature of αS/membrane interactions is of great interest. Understanding these interactions is a principle goal of the Sachs lab, and a combined computational and experimental strategy that brings together resources from MSI and the University of Minnesota’s Characterization Facility is being pioneered by Sachs’s PhD student, Anthony Braun.
It has recently become clear that amphipathic α‐helices, like αS, act by wedging between lipid headgroups and causing the membrane to curve, a morphological change necessary for a lipid vesicle to either bud or fuse. Many such proteins have been studied for their ability to cause gross‐deformations in vesicles (see the figure, above), namely the formation of lipid tubes (tubulation) or smaller vesicles (vesiculation). Theories have suggested that a helix must be sufficiently long and bind at a specific depth within the phospholipid bilayer in order to affect these changes.
The Sachs group is developing very large molecular simulations of amphipathic α‐helices bound to membranes in order to establish the relative importance of each of these attributes, as well as the contribution of helical flexibility, which this group has recently shown to contribute to membrane curvature in a unique way. The group is testing the hypothesis that the essential properties of a curvature‐inducing α‐helix, like αS, are not uniquely encoded in the primary sequence, but instead result from the sum of the protein’s physical attributes (length, hydrophobicity and flexibility). This research involves molecular dynamics computations on the supercomputers and results have been published recently in the Journal of the American Chemical Society (“alpha-Synuclein Induces Both Positive Mean Curvature and Negative Gaussian Curvature in Membranes,” A.R. Braun, E. Sevcsik, P. Chin, E. Rhoades, S. Tristram-Nagle, and J.N. Sachs, J Am Chem Soc 134, 2613-2620 (2012), DOI:10.1021/ja208316h) and the Journal of Biological Chemistry (“Curvature Dynamics of Alpha-Synuclein Familial Parkinson Disease Mutants: Molecular Simulations of the Micelle- and Bilayer-Bound Forms,” J.D. Perlmutter, A.R. Braun, and J.N. Sachs, J Biol Chem 284, 7177-7189 (2009), DOI:10.1074/jbc.M808895200).
Other work from the Sachs lab on the Tumor Necrosis Factor receptors has also utilized the MSI resources, and focuses on understanding conformation changes in these proteins to establish new therapeutic strategies for cancer and auto-inflammatory disease (“TNFR1 Signaling Is Associated With Backbone Conformational Changes of Receptor Dimers Consistent With Overactivation in the R92Q TRAPS Mutant,” A.K. Lewis, C.C. Valley, and J.N. Sachs, Biochemistry 51, 6545-6555 (2012), DOI:10.1021/bi3006626) and “Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Induces Death Receptor 5 Networks That Are Highly Organized,” C.C. Valley, A.K. Lewis, D.J. Mudaliar, J.D. Perlmutter, A.R. Braun, C.B. Karim, D.D. Thomas, J.R. Brody, and J.N. Sachs, J Biol Chem 287, 21265-21278 (2012), DOI:10.1074/jbc.M111.306480).
Figure Description: Building on their recent study that characterized the curvature fields induced in membranes by α-Synuclein (J Am Chem Soc 134, 2613-2620 (2012), DOI:10.1021/ja208316h), and relying upon the immense computational power of MSI, the Sachs group is running massive coarse-grained molecular dynamics simulations in order to study remodeling of the membrane by the protein. Shown is a snapshot with α-Synuclein (yellow beads) sitting atop a curved membrane (blue and pink beads). Water has been excluded from the image. The simulation was started with a flat membrane, but after 1 microsecond of calculated dynamics the curvature has become clear. The membrane is comprised of more than 50,000 fully hydrated lipids, requiring more than 4x106 total beads. Periodic images are included to illustrate the global topography (green beads). For these massive molecular simulations, the group takes advantage of MSI’s Itasca cluster, operating on 1024 cores (128 nodes, 8 processors per node), and achieving approximately 250 nanoseconds per 24-hour window.