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Review
. 2016 May;137(3):331-59.
doi: 10.1111/jnc.13570. Epub 2016 Mar 23.

The Contribution of Alpha Synuclein to Neuronal Survival and Function - Implications for Parkinson's Disease

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Free PMC article
Review

The Contribution of Alpha Synuclein to Neuronal Survival and Function - Implications for Parkinson's Disease

Matthew J Benskey et al. J Neurochem. .
Free PMC article

Abstract

The aggregation of alpha synuclein (α-syn) is a neuropathological feature that defines a spectrum of disorders collectively termed synucleinopathies, and of these, Parkinson's disease (PD) is arguably the best characterized. Aggregated α-syn is the primary component of Lewy bodies, the defining pathological feature of PD, while mutations or multiplications in the α-syn gene result in familial PD. The high correlation between α-syn burden and PD has led to the hypothesis that α-syn aggregation produces toxicity through a gain-of-function mechanism. However, α-syn has been implicated to function in a diverse range of essential cellular processes such as the regulation of neurotransmission and response to cellular stress. As such, an alternative hypothesis with equal explanatory power is that the aggregation of α-syn results in toxicity because of a toxic loss of necessary α-syn function, following sequestration of functional forms α-syn into insoluble protein aggregates. Within this review, we will provide an overview of the literature linking α-syn to PD and the knowledge gained from current α-syn-based animal models of PD. We will then interpret these data from the viewpoint of the α-syn loss-of-function hypothesis and provide a potential mechanistic model by which loss of α-syn function could result in at least some of the neurodegeneration observed in PD. By providing an alternative perspective on the etiopathogenesis of PD and synucleinopathies, this may reveal alternative avenues of research in order to identify potential novel therapeutic targets for disease modifying strategies. The correlation between α-synuclein burden and Parkinson's disease pathology has led to the hypothesis that α-synuclein aggregation produces toxicity through a gain-of-function mechanism. However, in this review, we discuss data supporting the alternative hypothesis that the aggregation of α-synuclein results in toxicity because of loss of necessary α-synuclein function at the presynaptic terminal, following sequestration of functional forms of α-synuclein into aggregates.

Keywords: Lewy body; Parkinson's disease; alpha-synuclein; dopamine; substantia nigra; synucleinopathy.

Figures

Figure 1
Figure 1
Normal and pathological subcellular distribution of α‐syn. (a) In healthy neurons, α‐syn is highly enriched within the presynaptic terminal. (b) As humans age, there is a distribution of α‐syn from the presynaptic terminal to the soma. This may predispose neurons to subsequent toxicity. (c) In PD, an initial insult (genetic mutation, oxidative stress, multiplications of SNCA gene, etc.,) induces the aggregation of α‐syn, resulting in loss of α‐syn function and subsequent toxicity leading to cell death. (d) Over‐expression of α‐syn results in increased α‐syn protein throughout the entire cell. Molecular crowding induces aggregation of α‐syn resulting in loss of α‐syn function and subsequent toxicity leading to cell death. (e) Knockdown of α‐syn decreases protein concentrations until a critical threshold is reached, below which loss of α‐syn function results in toxicity and cell death.
Figure 2
Figure 2
Proposed model of α‐syn function in the dopaminergic terminal. (a) In the absence of an action potential, α‐syn concentrations are high in the presynaptic terminal where it acts as a brake on chemical neurotransmission. A1) α‐syn inhibits DA synthesis by decreasing TH phosphorylation directly or by increasing PP2A activity. α‐syn also interacts with, and inhibits, AADC. A2) α‐syn aids in the sequestration of cytosolic DA by increasing the amount of VMAT on vesicles. A3) α‐syn prevents neurotransmitter release through interactions with synaptic vesicles and SNARE complex proteins to prevent trafficking and docking of vesicles with the presynaptic membrane. (A4) α‐syn facilitates the recycling of synaptic vesicles by mediating membrane bending during endocytosis, in order to (A5) maintain numbers of vesicles in the reserve (and possibly the readily releasable) vesicle pool. B1) Following neuronal stimulation and calcium influx, α‐syn rapidly disperses from the presynaptic terminal (B2) providing unimpeded vesicular trafficking and exocytosis for efficient neurotransmitter release. (B3) The absence of α‐syn disinhibits TH and AADC, allowing DA synthesis to replenish DA released during synaptic transmission. Upon repolarization, α‐syn repopulates the terminal to perform the actions listed in panel A to terminate chemical neurotransmission. (c) The aggregation of α‐syn in PD results in a loss of α‐syn function and subsequent increased cytosolic DA. (C1) Loss of α‐syn disinhibits TH and AADC, resulting in increased DA synthesis with a corresponding (C2) decrease in VMAT levels, and (C3) unregulated trafficking of synaptic vesicles. (C4) Loss of α‐syn function impairs endocytic vesicular recycling, (C5) decreasing the size of the vesicular pool. The net result is increased cytosolic DA, with a concomitant inability to efficiently sequester DA into synaptic vesicles. Increased cytosolic DA auto‐oxidizes to produce ROS and DA quinones. DA quinones react with sulfhydryl groups in proteins, forming DA‐cysteinyl adducts that covalently modify proteins, impairing enzymatic function. ROS oxidize proteins and lipids. DA‐cysteinyl adducts and ROS inhibit the electron transport chain, resulting in increased oxidative stress and opening of the mitochondrial permeability pore, as well as decreasing enzymatic break down of DA to DOPAC, further increasing cytosolic DA. Increased ROS and the formation of DA‐α‐syn adducts promote α‐syn aggregation. Together, an initial loss of α‐syn function can initiate a vicious cycle of toxicity ultimately resulting in cell death. Abbreviations: tyrosine hydroxylase (TH), aromatic amino acid decarboxylase (AADC), dopamine (DA), dihydroxyphenylalanine (DOPA), protein phosphatase 2A (PP2A), vesicular monoamine transporter (VMAT), dopamine transporter (DAT), voltage gated calcium channel (VGCC), reactive oxygen species (ROS), dopamine quinone (DA‐Q).
Figure 3
Figure 3
Nigral neurodegeneration due to loss of α‐syn translates across species and knockdown approaches. (a and b) Adult mice were injected in the left substantia nigra (SNc) with adeno‐associated virus (rAAV) 2/5 expressing a shRNA targeting mouse α‐syn (A) or a scrambled control shRNA(Scr) (B) (1.5 μL of 2.6 × 1012 vector genomes/mL). (c) 28‐days following vector injection animals were sacrificed and numbers of tyrosine hydroxylase neurons in the SNc were quantified using unbiased stereology. rAAV‐mediated expression of α‐syn shRNA results in an approximate 30% loss of neurons of the SNc (expressed as percent of intact hemisphere). * Indicates significantly different than scrambled shRNA control (p < 0.05). (d) Several microRNA sequences targeting rat α‐syn were evaluated in vitro. The microRNA achieving the most efficient knockdown of α‐syn in vitro was packaged into rAAV2/5 and injected in to the left SNc of adult rats (1.5 μL of 1 × 1012 vector genomes/mL). MicroRNA‐mediated knockdown of α‐syn results in a robust reduction of tyrosine hydroxylase neurons within the injected SNc.

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