Small molecule-mediated stabilization of vesicle-associated helical α-synuclein inhibits pathogenic misfolding and aggregation

Abstract

α-synuclein is an abundant presynaptic protein that is important for regulation of synaptic vesicle trafficking, and whose misfolding plays a key role in Parkinson's disease. While α-synuclein is disordered in solution, it folds into a helical conformation when bound to synaptic vesicles. Stabilization of helical, folded α-synuclein might therefore interfere with α-synuclein-induced neurotoxicity. Here we show that several small molecules, which delay aggregation of α-synuclein in solution, including the Parkinson's disease drug selegiline, fail to interfere with misfolding of vesicle-bound α-synuclein. In contrast, the porphyrin phtalocyanine tetrasulfonate directly binds to vesicle-bound α-synuclein, stabilizes its helical conformation and thereby delays pathogenic misfolding and aggregation. Our study suggests that small-molecule-mediated stabilization of helical vesicle-bound α-synuclein opens new possibilities to target Parkinson's disease and related synucleinopathies.

Effects of impaired membrane interactions on α-synuclein aggregation and neurotoxicity

“…However, an increase in the exposed state population is not itself sufficient for membrane-induced aggregation or neurotoxicity, as disrupting interactions between neighboring exposed conformers could impede the formation of toxic aggregates at the membrane surface. Collectively, our findings provide a rationale for alleviating aSyn neurotoxicity in PD and other synucleinopathy disorders by stabilizing aSyn-membrane interactions to favor the hidden state (Fonseca-Ornelas et al, 2014), or by interfering with the association of exposed conformers at the membrane surface.…”

Heme Stabilization of α-Synuclein Oligomers during Amyloid Fibril Formation

“…Firstly, the membrane composition may not serve as a fair representation of the physiological membrane, or even a membrane favorable for αSyn interactions. Others have shown αSyn interacts with small unilamellar vesicles comprised of POPC/POPA or DOPC:DOPS:DOPE 23 . The size of the vesicles used in our study may also have been a factor.…”

“…1A), and porphyrin, interactions with αSyn may play a role in its pathophysiology and can be inhibitors of fibril formation with IC 50 values in the low micromolar range 21–23 . Biochemical analysis revealed the formation of soluble oligomeric αSyn when incubated with heme, suggesting that this may be the mechanism by which filament formation is inhibited 21 .…”

Synaptic Vesicle-Recycling Machinery Components as Potential Therapeutic Targets

“…This hints at a role for dynamic phosphorylation on a-synuclein's function in synaptic vesicle recycling and disease progression. A small-molecule screen yielded a compound that targets vesicle-bound a-synuclein and inhibits its aggregation (Fonseca-Ornelas et al, 2014). It is yet to be seen how this affects a-synuclein's effect on synaptic vesicle recycling; however, similar methods can be used to find other modulations of a-synuclein function.…”