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      Quality Over Quantity: Advantages of Using Alpha-Synuclein Preformed Fibril Triggered Synucleinopathy to Model Idiopathic Parkinson’s Disease

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          Abstract

          Animal models have significantly advanced our understanding of Parkinson’s disease (PD). Alpha-synuclein (α-syn) has taken center stage due to its genetic connection to familial PD and localization to Lewy bodies, one pathological hallmark of PD. Animal models developed on the premise of elevated alpha-synuclein via germline manipulation or viral vector-mediated overexpression are used to investigate PD pathophysiology and vet novel therapeutics. While these models represented a step forward compared to their neurotoxicant model predecessors, they rely on overexpression of supraphysiological levels of α-syn to trigger toxicity. However, whereas SNCA-linked familial PD is associated with elevated α-syn, elevated α-syn is not associated with idiopathic PD. Therefore, the defining feature of the α-syn overexpression models may fail to appropriately model idiopathic PD. In the last several years a new model has been developed in which α-syn preformed fibrils are injected intrastriatally and trigger normal endogenous levels of α-syn to misfold and accumulate into Lewy body-like inclusions. Following a defined period of inclusion accumulation, distinct phases of neuroinflammation and progressive degeneration can be detected in the nigrostriatal system. In this perspective, we highlight the fact that levels of α-syn achieved in overexpression models generally exceed those observed in idiopathic and even SNCA multiplication-linked PD. This raises the possibility that supraphysiological α-syn expression may drive pathophysiological mechanisms not relevant to idiopathic PD. We argue in this perspective that synucleinopathy triggered to form within the context of normal α-syn expression represents a more faithful animal model of idiopathic PD when examining the role of neuroinflammation or the relationship between a-syn aggregation and toxicity.

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          alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies.

          Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown composition. We show here that Lewy bodies and Lewy neurites from Parkinson's disease and dementia with Lewy bodies are stained strongly by antibodies directed against amino-terminal and carboxyl-terminal sequences of alpha-synuclein, showing the presence of full-length or close to full-length alpha-synuclein. The number of alpha-synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites. Staining for alpha-synuclein thus will replace staining for ubiquitin as the preferred method for detecting Lewy bodies and Lewy neurites. We have isolated Lewy body filaments by a method used for the extraction of paired helical filaments from Alzheimer's disease brain. By immunoelectron microscopy, extracted filaments were labeled strongly by anti-alpha-synuclein antibodies. The morphologies of the 5- to 10-nm filaments and their staining characteristics suggest that extended alpha-synuclein molecules run parallel to the filament axis and that the filaments are polar structures. These findings indicate that alpha-synuclein forms the major filamentous component of Lewy bodies and Lewy neurites.
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            G51D α-synuclein mutation causes a novel parkinsonian-pyramidal syndrome.

            To date, 3 rare missense mutations in the SNCA (α-synuclein) gene and the more frequent duplications or triplications of the wild-type gene are known to cause a broad array of clinical and pathological symptoms in familial Parkinson disease (PD). Here, we describe a French family with a parkinsonian-pyramidal syndrome harboring a novel heterozygous SNCA mutation. Whole exome sequencing of DNA from 3 patients in a 3-generation pedigree was used to identify a new PD-associated mutation in SNCA. Clinical and pathological features of the patients were analyzed. The cytotoxic effects of the mutant and wild-type proteins were assessed by analytical ultracentrifugation, thioflavin T binding, transmission electron microscopy, cell viability assay, and caspase-3 activation. We identified a novel SNCA G51D (c.152 G>A) mutation that cosegregated with the disease and was absent from controls. G51D was associated with an unusual PD phenotype characterized by early disease onset, moderate response to levodopa, rapid progression leading to loss of autonomy and death within a few years, marked pyramidal signs including bilateral extensor plantar reflexes, occasionally spasticity, and frequently psychiatric symptoms. Pathological lesions predominated in the basal ganglia and the pyramidal tracts and included fine, diffuse cytoplasmic inclusions containing phospho-α-synuclein in superficial layers of the cerebral cortex, including the entorhinal cortex. Functional studies showed that G51D α-synuclein oligomerizes more slowly and its fibrils are more toxic than those of the wild-type protein. We have identified a novel SNCA G51D mutation that causes a form of PD with unusual clinical, neuropathological, and biochemical features. Copyright © 2013 American Neurological Association.
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              Addition of exogenous α-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous α-synuclein to Lewy body and Lewy neurite-like aggregates.

              This protocol describes a primary neuronal model of formation of α-synuclein (α-syn) aggregates that recapitulate features of the Lewy bodies and Lewy neurites found in Parkinson's disease brains and other synucleinopathies. This model allows investigation of aggregate formation, their impact on neuron function, and development of therapeutics. Addition of preformed fibrils (PFFs) synthesized from recombinant α-syn to neurons seeds the recruitment of endogenous α-syn into aggregates characterized by detergent insolubility and hyperphosphorylation. Aggregate formation follows a lag phase of 2-3 d, followed by formation in axons by days 4-7, spread to somatodendritic compartments by days 7-10 and neuron death ~14 d after PFF addition. Here we provide methods and highlight the crucial steps for PFF formation, PFF addition to cultured hippocampal neurons and confirmation of aggregate formation. Neurons derived from various brain regions from nontransgenic and genetically engineered mice and rats can be used, allowing interrogation of the effect of specific genes on aggregate formation.
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                Author and article information

                Contributors
                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                04 September 2018
                2018
                : 12
                : 621
                Affiliations
                [1] 1Department of Translational Science and Molecular Medicine, Michigan State University , Grand Rapids, MI, United States
                [2] 2Mercy Health Hauenstein Neuroscience Medical Center , Grand Rapids, MI, United States
                Author notes

                Edited by: Ruth G. Perez, Texas Tech University Health Sciences Center, United States

                Reviewed by: Rehanak K. Leak, Duquesne University, United States; Philipp Janker Kahle, Hertie-Institut für klinische Hirnforschung (HIH), Germany

                *Correspondence: Caryl E. Sortwell, caryl.sortwell@ 123456hc.msu.edu

                This article was submitted to Neurodegeneration, a section of the journal Frontiers in Neuroscience

                Article
                10.3389/fnins.2018.00621
                6132025
                30233303
                396feb53-41fc-4237-973e-7bd4ffff4816
                Copyright © 2018 Duffy, Collier, Patterson, Kemp, Fischer, Stoll and Sortwell.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 May 2018
                : 17 August 2018
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 92, Pages: 10, Words: 0
                Funding
                Funded by: National Institute of Neurological Disorders and Stroke 10.13039/100000065
                Award ID: NS099416
                Categories
                Neuroscience
                Perspective

                Neurosciences
                parkinson’s disease,alpha-synuclein,preformed fibrils,synucleinopathy,animal models

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