The many faces of α-synuclein: from structure and toxicity to therapeutic target - PubMed (original) (raw)

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The many faces of α-synuclein: from structure and toxicity to therapeutic target

Hilal A Lashuel et al. Nat Rev Neurosci. 2013 Jan.

Abstract

Disorders characterized by α-synuclein (α-syn) accumulation, Lewy body formation and parkinsonism (and in some cases dementia) are collectively known as Lewy body diseases. The molecular mechanism (or mechanisms) through which α-syn abnormally accumulates and contributes to neurodegeneration in these disorders remains unknown. Here, we provide an overview of current knowledge and prevailing hypotheses regarding the conformational, oligomerization and aggregation states of α-syn and their role in regulating α-syn function in health and disease. Understanding the nature of the various α-syn structures, how they are formed and their relative contributions to α-syn-mediated toxicity may inform future studies aiming to develop therapeutic prevention and intervention.

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Figures

Figure 1

Figure 1. Functional properties of α-synuclein

a, b | Wide field and magnified images of cultured cortical neurons from a postnatal day 1 wild-type mouse showing a neuronal dendrite (as revealed by MAP2 immunostaining; red) opposed to α-synuclein (α-syn)-positive presynaptic densities (green), indicating that α-syn is located in the presynaptic terminals. c | The schematic depicts the various roles of α-syn at the pre-synaptic terminal in the regulation of vesicle trafficking and vesicle refilling (α-syn; blue), as well as the interaction with membrane-associated t-SNARE or the vesicle-associated v-SNARE proteins and neurotransmitter release. Accumulation of α-syn induces an impairment of neurotransmitter release, vesicle recycling and trafficking between synaptic buttons and influence t-SNARE complex assembly stability (α-syn; red), whereas its depletion induces an impairment of vesicle trafficking between the reserve pool and the ready releasable pool and a deficiency in vesicle refilling and neurotransmitter uptake.

Figure 2

Figure 2. Biochemical structure of α-synuclein and its pathological distribution in Parkinson's disease and a mouse model of Lewy body disease

a | Computer-generated model of α-synuclein (α-syn) representing the N-terminal α helices, non-amyloid-β component of Alzheimer's disease amyloid plaques (NAC; depicted in red), and unstructured C-terminal regions. b | Western blot identifying α-syn in brain homogenates from control and Lewy body disease cases that were divided into cytosolic and particulate fractions. α-Syn migrated to 57–60 kDa as well as to 14 kDa in the particulate but not cytosolic fraction due to the different conformational states of the protein. c, d | α-Syn is present in Lewy bodies, neurites, synapses and astroglia in dementia with Lewy bodies (DLB) and Parkinson's disease (PD) and in PDGFβ-human _α_-syn wild type transgenic mice, as indicated by arrows.

Figure 3

Figure 3. Cellular events controlling intracellular α-synuclein levels and possible therapeutic strategies to combat α-synuclein accumulation and transmission

Intracellular α-synuclein (α-syn) levels are tightly regulated by the balance between the rates of α-syn synthesis, clearance and aggregation. a | Abnormalities affecting α-syn synthesis, including SNCA multiplication and polymorphisms, may increase intracellular α-syn levels and induce its accumulation. Accumulation may also be caused by a failure to degrade α-syn. Clearance deficits might arise from failure of the ubiquitin – proteasome system, chaperone-mediated autophagy dysfunction (induced by Parkinson disease-linked mutations) or dysfunction of proteases (neurosin or matrix metalloprotease 9). Finally, certain SNCA mutations, post-translational modifications, oxidative stress, toxins and interaction with oxidized dopamine increase the propensity of α-syn to aggregate and accumulate. b | Targeted mechanisms to reduce α-syn accumulation include decreasing protein synthesis by using Rep1, siRNA or miRNA. Accumulation may also be decreased by activating mechanisms or proteins involved in clearance, such as autophagy, the proteasome, neurosin, MMP9 and heat shock proteins. Additionally, aggregation of α-syn can be decreased using anti-aggregating, antioxidant, or post-translational modification approaches. Finally, immunotherapy may be used to block transmission and oligomer formation.

Figure 4

Figure 4. Mechanisms of α-synuclein aggregation and propagation

Unfolded monomers of α-synuclein (α-syn) interact to form two types of dimers: anti-parallel dimers, which do not propagate, and parallel dimmers, which do propagate. A dynamic equilibrium is established between unfolded monomers and both forms of dimers. Interestingly, this process can take place either in the cytoplasm or in association with the cellular membrane. Propagating α-syn dimers can grow by the addition of unfolded monomers and generate ring-like oligomers and oligomers. Ring-like α-syn oligomers interact with the cytoplasmic membrane and form trans-membrane pores, inducing abnormal intracellular calcium influx. Cytoplasmic α-syn oligomers grow by the addition of soluble monomers, forming small amyloid fibrils and then longer fibrils. The accumulation of these amyloid fibrils leads to the formation of intracellular inclusions called Lewy bodies. During α-syn fibrillogenesis and aggregation, the intermediate species (oligomers and amyloid fibrils) are highly toxic, affecting mitochondrial function, endoplasmic reticulum (ER) – Golgi trafficking, protein degradation and/or synaptic transmission. These intracellular effects are thought to induce neurodegeneration. Interestingly, α-syn oligomers and fibrils, as well as the monomers, can be transferred between cells and induce disease spreading to other brain regions. Spreading mechanisms are multiple and can occur via endocytosis, direct penetration, transynaptic transmission, or via membrane receptors.

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