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Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies

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Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies cells Review Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies Inês C. Brás 1 and Tiago F. Outeiro 1,2,3,4,* 1 Center for Biostructural Imaging of Neurodegeneration, Department of Experimental Neurodegeneration, University Medical Center Göttingen, 37075 Göttingen, Germany; [email protected] 2 Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany 3 Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK 4 Scientific Employee with a Honorary Contract at Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 37075 Göttingen, Germany * Correspondence: [email protected]; Tel.: +49-(0)-551-391-3544; Fax: +49-(0)-551-392-2693 Abstract: The accumulation of misfolded alpha-synuclein (aSyn) throughout the brain, as Lewy pathology, is a phenomenon central to Parkinson’s disease (PD) pathogenesis. The stereotypical distribution and evolution of the pathology during disease is often attributed to the cell-to-cell transmission of aSyn between interconnected brain regions. The spreading of conformationally distinct aSyn protein assemblies, commonly referred as strains, is thought to result in a variety of clin- ically and pathologically heterogenous diseases known as synucleinopathies. Although tremendous progress has been made in the field, the mechanisms involved in the transfer of these assemblies between interconnected neural networks and their role in driving PD progression are still unclear. Here, we present an update of the relevant discoveries supporting or challenging the prion-like spreading hypothesis. We also discuss the importance of aSyn strains in pathology progression and the various putative molecular mechanisms involved in cell-to-cell protein release. Understanding Citation: Brás, I.C.; Outeiro, T.F. the pathways underlying aSyn propagation will contribute to determining the etiology of PD and Alpha-Synuclein: Mechanisms of Release and Pathology Progression in related synucleinopathies but also assist in the development of new therapeutic strategies. Synucleinopathies. Cells 2021, 10, 375. https://doi.org/10.3390/ Keywords: Parkinson’s disease; alpha-synuclein; prion-like spreading; cell-to-cell transfer; cells10020375 neurodegeneration Academic Editor: Cristine Alves Da Costa Received: 23 January 2021 1. Introduction Accepted: 9 February 2021 More than 200 years ago, James Parkinson described some of the clinical symptoms of Published: 12 February 2021 the disease that, later, was named as Parkinson’s disease (PD) in “Essay on the Shaking Palsy” [1]. Clinically, patients exhibit a progressive deterioration of neurological functions Publisher’s Note: MDPI stays neutral such as cognition and motor function, but also sleep disorders (rapid eye movement with regard to jurisdictional claims in (REM) sleep disorder), hyposmia, and autonomic failure [2]. The motor symptoms result published maps and institutional affil- from the severe loss of dopaminergic neurons in the substantia nigra pars compacta iations. (SNpc) and the consequent deregulation of basal ganglia activity [3]. PD is one of several synucleinopathies, which are a diverse group of neurodegenerative diseases known for the deposition of misfolded alpha-synuclein (aSyn) in the brain [4,5]. aSyn can accumulate in Lewy bodies (LBs) or Lewy neurites (LNs), in Lewy body diseases, or in glial cytoplasmic Copyright: © 2021 by the authors. inclusions (GCIs), in multiple system atrophy (MSA) [6–8]. Licensee MDPI, Basel, Switzerland. LBs inclusions contain high levels of aSyn phosphorylated at serine 129 (pS129). In This article is an open access article addition, it is estimated that 10 to 30% aSyn in LBs is truncated in the N- or C-terminal distributed under the terms and regions [9–11]. In the brain, synaptic dysfunction and neuronal loss are thought to precede conditions of the Creative Commons the formation of aSyn inclusions. Attribution (CC BY) license (https:// Detailed observations of aggregated aSyn in post-mortem brain tissue from patients creativecommons.org/licenses/by/ 4.0/). at different clinical stages of PD form the basis for the hypothesis that Lewy pathology Cells 2021, 10, 375. https://doi.org/10.3390/cells10020375 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 22 Detailed observations of aggregated aSyn in post-mortem brain tissue from patients Cells 2021, 10, 375 at different clinical stages of PD form the basis for the hypothesis that Lewy pathology2 of 19 can progress, as disease progresses, through interconnected brain regions [12–14]. The putative neurotoxicity exerted by aSyn aggregates, and due to cell-to-cell transfer, it is correlated with increased severity of the clinical symptoms of PD [15]. Although the molecularcan progress, mechanisms as disease involved progresses, in disease through progression interconnected remain brain unclear, regions several [12 studies–14]. The in humanputative tissue neurotoxicity and in animal exerted models by aSyn are aggregates,consistent with and duethe cell-to-cell to cell-to-cell transmission transfer, it of is pathologicalcorrelated with aSyn increased [16]. Importantly, severity of recent the clinical evidence symptoms suggests of that PD transfer [15]. Although of aSyn ag- the molecular mechanisms involved in disease progression remain unclear, several studies gregates with disease-specific conformations, referred to as strains, may partly explain in human tissue and in animal models are consistent with the cell-to-cell transmission the existence of distinct synucleinopathies (Figure 1) [17–20]. Similarly to what happens of pathological aSyn [16]. Importantly, recent evidence suggests that transfer of aSyn in prion diseases, aSyn strains are thought to template the aggregation of native aSyn into aggregates with disease-specific conformations, referred to as strains, may partly explain pathological forms, resulting in the spreading and progression of disease pathology [21]. the existence of distinct synucleinopathies (Figure1)[ 17–20]. Similarly to what happens in Currently, the molecular mechanisms and factors modulating aSyn aggregation remain prion diseases, aSyn strains are thought to template the aggregation of native aSyn into obscure, highlighting the need for further studies. pathological forms, resulting in the spreading and progression of disease pathology [21]. Currently, the molecular mechanisms and factors modulating aSyn aggregation remain obscure, highlighting the need for further studies. Figure 1. Model for templated misfolding of endogenous alpha-synucleinalpha-synuclein (aSyn). Under pathol pathologicalogical conditions, due to genetic or environmental factors, natively natively unfolded unfolded aSyn aSyn monomers monomers are are able able to to self-aggregate self-aggregate in in pathological pathological oligomers. oligomers. These species cancan bebe extended extended into into protofibrils protofibrils and and other other mature matu speciesre species such such as fibrils as fibrils or ribbons or ribbons that depositthat deposit into inclusion into in- clusionbodies asbodies Lewy as bodies Lewy (LBs) bodies and (LBs) Lewy and neurites Lewy (LNs).neurites Although (LNs). Although the biophysical the biophysical properties properties and formation and offormation ribbons areof ribbons are still not well understood, the other aSyn assemblies coexist in a dynamic equilibrium and can be transformed still not well understood, the other aSyn assemblies coexist in a dynamic equilibrium and can be transformed into higher- into higher- or lower-order conformations. or lower-order conformations. InIn this review,review, we we focus focus on on selected selected studies studies supporting supporting the prion-likethe prion-like behavior behavior of aSyn of aSynand onand the on molecular the molecular mechanisms mechanisms involved involved in the spreadingin the spreading of pathology of pathology during diseaseduring diseaseprogression. progression. Further Further clarification clarification of these of concepts these concepts will assist will in assist the development in the development of new oftherapeutic new therapeutic strategies strategies aimed at aimed preventing at prev diseaseenting progressiondisease progression in synucleinopathies. in synucleinopa- thies. 2. aSyn: From Function to Neurotoxicity 2. aSyn:The From synuclein Function family to comprisesNeurotoxicity three small soluble proteins, alpha-, beta- and gamma- synuclein,The synuclein that bind family to phospholipid comprises membranes three small [22 ].soluble aSyn isproteins, encoded alpha-, by the SNCA beta- geneand gamma-synuclein,and is composed of that three bind distinct to phospholipid domains, which membranes are defined [22]. on aSyn their aminois encoded acid compo-by the SNCAsition: gene The N-terminaland is composed lipid-binding of three domain,distinct domains, an amyloid-binding which are defined central on region their (NAC),amino acidand acomposition: C-terminal disordered the N-terminal region lipid-bind [23]. Theing N-terminal domain, domain an amyloid-binding is positively charged central andre- gioncontains (NAC), seven and amphipathic a C-terminal repeats disordered containing region a conserved[23]. The N-terminal KTKEGV hexamericdomain is motif,posi- tivelywhich charged enables and an alpha-helicalcontains seven structure amphipat andhic interactions repeats containing with membranes a conserved [24 KTKEGV,25]. The hexamericcentral
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