Modulating membrane binding of α-synuclein as a therapeutic strategy

α-Synuclein aggregation is a pathological hallmark of Parkinson’s disease (PD), Lewy body dementia, multiple system atrophy, and a variety of other synucleinopathies (1). The occurrence of familial PD due to α-synuclein mutations, gene duplication and triplication, as well as polymorphisms in regulatory elements of the α-synuclein gene, supports a causative role of α-synuclein in these neurodegenerative diseases (reviewed in ref. 2). In addition, a prion-like spread of α-synuclein pathology has been proposed, by propagation of neurotoxic α-synuclein aggregates from one neuron to the other (3). Attenuating or stopping aggregation of α-synuclein is thus a highly pursued strategy to combat pathology in these diseases (Fig. 1). A number of factors have been reported to influence the aggregation propensity of α-synuclein, including oxidative stress, posttranslational modifications in α-synuclein, and increased local concentration. Proposed strategies to stop or reduce α-synuclein aggregation include enhancing the levels of heat shock proteins to stabilize protein folding, using compounds with antioxidant or antiaggregant activity, promoting intracellular degradation of α-synuclein, or immunotherapies to clear α-synuclein (reviewed in ref. 4). Fig. 1. Physiological and pathological conformations of α-synuclein and strategies to combat α-synuclein aggregation and toxicity. Physiologically, α-synuclein exists in an equilibrium between α-helical multimers bound to synaptic vesicles, and a natively unfolded monomeric state. Membranous α-synuclein clusters synaptic vesicles and chaperones SNARE complex assembly to maintain neurotransmitter release. Under pathological conditions, partial membrane binding of α-synuclein increases the local concentration of the aggregation-prone NAC region, allowing seeding of α-synuclein aggregation. Similarly, cytosolic monomeric α-synuclein spontaneously forms oligomers, which eventually build up as amyloid fibrils and spread to neurons and glia in a prion-like manner. Various therapeutic strategies are being pursued to prevent α-synuclein–mediated pathology, by modulating α-synuclein aggregation, … [↵][1]1To whom correspondence should be addressed. Email: jab2058{at}med.cornell.edu. [1]: #xref-corresp-1-1