Abstract
Synucleinopathies are neurological disorders associated with α-synuclein overexpression and aggregation. While it is well-established that overexpression of wild type α-synuclein (α-syn-140) leads to cellular toxicity and neurodegeneration, much less is known about other naturally occurring α-synuclein splice isoforms. In this study we provide the first detailed examination of the synaptic effects caused by one of these splice isoforms, α-synuclein-112 (α-syn-112). α-Syn-112 is produced by an in-frame excision of exon 5, resulting in deletion of amino acids 103–130 in the C-terminal region. α-Syn-112 is upregulated in the substantia nigra, frontal cortex, and cerebellum of parkinsonian brains and higher expression levels are correlated with susceptibility to Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple systems atrophy (MSA). We report here that α-syn-112 binds strongly to anionic phospholipids when presented in highly curved liposomes, similar to α-syn-140. However, α-syn-112 bound significantly stronger to all phospholipids tested, including the phosphoinositides. α-Syn-112 also dimerized and trimerized on isolated synaptic membranes, while α-syn-140 remained largely monomeric. When introduced acutely to lamprey synapses, α-syn-112 robustly inhibited synaptic vesicle recycling. Interestingly, α-syn-112 produced effects on the plasma membrane and clathrin-mediated synaptic vesicle endocytosis that were phenotypically intermediate between those caused by monomeric and dimeric α-syn-140. These findings indicate that α-syn-112 exhibits enhanced phospholipid binding and oligomerization in vitro and consequently interferes with synaptic vesicle recycling in vivo in ways that are consistent with its biochemical properties. This study provides additional evidence suggesting that impaired vesicle endocytosis is a cellular target of excess α-synuclein and advances our understanding of potential mechanisms underlying disease pathogenesis in the synucleinopathies.
Highlights
Synucleinopathies are a class of neurological disorders linked to overexpression and aggregation of α-synuclein, and they include Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB), and Multiple Systems Atrophy (MSA)
When overexpressed at mammalian synapses to levels comparable to those in familial PD, α-syn-140 impaired synaptic vesicle trafficking (Nemani et al, 2010; Scott et al, 2010), and altered the composition of presynaptic proteins (Scott et al, 2010). In line with these findings, we previously reported that acute introduction of α-syn-140 at a classical vertebrate synapse, the lamprey reticulospinal (RS) synapse, impaired synaptic vesicle recycling mediated by clathrin-mediated endocytosis and possibly bulk endocytosis (Busch et al, 2014; Medeiros et al, 2017; Banks et al, 2020)
We began by comparing the lipid binding properties of α-syn112 and α-syn-140. α-Syn-140 comprises an amphipathic alphahelical region that is involved in lipid binding (a.a. 1–101); a non-amyloid component (NAC) domain that is involved in selfassociation (a.a. 61–95); and a less structured acidic C-terminal domain (a.a. 102–140) (Figure 1A)
Summary
Synucleinopathies are a class of neurological disorders linked to overexpression and aggregation of α-synuclein, and they include Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB), and Multiple Systems Atrophy (MSA). Consistent with enhanced membrane binding and oligomerization, α-syn112 inhibited synaptic vesicle recycling at lamprey synapses and produced a phenotype that was intermediate between monomeric and dimeric α-syn-140 (Busch et al, 2014; Medeiros et al, 2017, 2018; Banks et al, 2020). These findings implicate α-syn-112 in inducing defective synaptic vesicle trafficking, which may lead to cellular toxicity in the synucleinopathies
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