Modulating membrane binding of α-synuclein as a therapeutic strategy

Abstract

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).However, none of these approaches has had success in translation to the clinic, and treatments for PD remain symptomatic, focusing on treating the movement disorder symptoms associated with loss of dopaminergic neurons in the substantia nigra pars compacta. Treatment of the nonmotor symptoms is much more challenging and less established, and no therapy is available that slows down or stops the progression of PD. In PNAS, Perni et al. (5) report an inhibitory effect of squalamine-an antimicrobial agent derived from the dogfish shark-on α-synuclein aggregation in vitro and toxicity in vivo, via displacing α-synuclein from phospholipid membranes.Physiologically, α-synuclein exists in a dynamic equilibrium between a natively unfolded cytosolic state and a multimeric membrane-bound state on synaptic vesicles (6, 7). The N-terminal sequence of α-synuclein forms an amphipathic α-helix that mediates association of α-synuclein with lipid membranes (8). This region also contains the non-amyloid-β component (NAC), an area believed to be responsible for α-synuclein aggregation (9). The interaction between α-synuclein and synaptic membranes is believed to be a key feature for mediating its proposed cellular functions: the presynaptic localization of α-synuclein, its interaction with synaptic vesicles and synaptobrevin-2, its SNARE complex-chaperoning activity, its effects on vesicle clustering, and its changes during periods of song acquisition-related synaptic rearrangements in birds (reviewed in ref. 10) strongly suggest that α-synuclein plays a role in neurotransmitter 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 syn...

Harpagide, a natural product, promotes synaptic vesicle release as measured by nanoelectrode amperometry

“…Recent studies suggested that a-Syn also enhances vesicle membrane stabilization and promote synaptic vesicle recycling, whereas P-Syn has the converse effect. [59][60][61] Our amperometric results fully support these statements on quantitative grounds. Indeed, in addition to enhancing the average number of released molecules per exocytotic spike ( Fig.…”

Gastrointestinal Immunity and Alpha-Synuclein

“…␣S knockout mice are surprisingly healthy and do not exhibit a strong neurological phenotype, even when all three synuclein genes are removed [40]. Since ␣S is known to associate with secretory vesicles, much of the research in these models has focused on neurotransmitter vesicle dynamics [41]. Indeed, subtle differences in vesicle behavior dependent on the presence or absence of ␣S have been detected [42].…”

Rationally Designed Variants of α-Synuclein Illuminate Its in vivo Structural Properties in Health and Disease

“…Disturbed αS homeostasis, however, may be corrected in the future by interfering with αS membrane-interactions. Interestingly, the drug squalamine has recently been reported to displace αS from lipid vesicles, thereby inhibiting aggregation and reducing toxicity ( Perni et al, 2017 ; Pineda and Burré, 2017 ). However, an A30P carrier may not benefit from such a treatment because A30P already exhibits decreased membrane binding.…”