Modeling Parkinson's Disease With the Alpha-Synuclein Protein
Top Cited Papers
Open Access
- 22 April 2020
- journal article
- review article
- Published by Frontiers Media SA in Frontiers in Pharmacology
- Vol. 11, 356
- https://doi.org/10.3389/fphar.2020.00356
Abstract
Alpha-synuclein (alpha-Syn) is a key protein involved in Parkinson's disease (PD) pathology. PD is characterized by the loss of dopaminergic neuronal cells in the substantia nigra pars compacta and the abnormal accumulation and aggregation of alpha-Syn in the form of Lewy bodies and Lewy neurites. More precisely, the aggregation of alpha-Syn is associated with the dysfunctionality and degeneration of neurons in PD. Moreover, mutations in the SNCA gene, which encodes alpha-Syn, cause familial forms of PD and are the basis of sporadic PD risk. Given the role of the alpha-Syn protein in the pathology of PD, animal models that reflect the dopaminergic neuronal loss and the widespread and progressive formation of alpha-Syn aggregates in different areas of the brain constitute a valuable tool. Indeed, animal models of PD are important for understanding the molecular mechanisms of the disease and might contribute to the development and validation of new therapies. In the absence of animal models that faithfully reproduce human PD, in recent years, numerous animal models of PD based on alpha-Syn have been generated. In this review, we summarize the main features of the alpha-Syn pre-formed fibrils (PFFs) model and recombinant adeno-associated virus vector (rAAV) mediated alpha-Syn overexpression models, providing a detailed comparative analysis of both models. Here, we discuss how each model has contributed to our understanding of PD pathology and the advantages and weakness of each of them. Significance Here, we show that injection of alpha-Syn PFFs and overexpression of alpha-Syn mediated by rAAV lead to a different pattern of PD pathology in rodents. First, alpha-Syn PFFs models trigger the Lewy body-like inclusions formation in brain regions directly interconnected with the injection site, suggesting that there is an inter-neuronal transmission of the alpha-Syn pathology. In contrast, rAAV-mediated alpha-Syn overexpression in the brain limits the alpha-Syn aggregates within the transduced neurons. Second, phosphorylated alpha-Syn inclusions obtained with rAAV are predominantly nuclear with a punctate appearance that becomes diffuse along the neuronal fibers, whereas alpha-Syn PFFs models lead to the formation of cytoplasmic aggregates of phosphorylated alpha-Syn reminiscent of Lewy bodies and Lewy neurites.Keywords
Funding Information
- Ministerio de Ciencia, Innovación y Universidades (SAF2016-78207-R , EuroNanomed, ref PCIN-2015-098)
- Ministerio de Sanidad, Servicios Sociales e Igualdad (Instituto de Salud Carlos III (ISCIII), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas [CIBERNED] (CB06/05/ 0055, PNSD-2016I033)
- Fundación Ramón Areces (172275)
- Consejo Superior de Investigaciones Científicas (JAE-Intro to Mónica Gómez Benito)
This publication has 136 references indexed in Scilit:
- Caudo‐rostral brain spreading of α‐synuclein through vagal connectionsEMBO Molecular Medicine, 2013
- Living on the edge with too many mouths to feed: Why dopamine neurons dieMovement Disorders, 2012
- Nigrostriatal overabundance of α-synuclein leads to decreased vesicle density and deficits in dopamine release that correlate with reduced motor activityActa Neuropathologica, 2012
- Aggregation of αSynuclein promotes progressive in vivo neurotoxicity in adult rat dopaminergic neuronsActa Neuropathologica, 2011
- Exogenous α-Synuclein Fibrils Induce Lewy Body Pathology Leading to Synaptic Dysfunction and Neuron DeathNeuron, 2011
- Gaucher Disease Glucocerebrosidase and α-Synuclein Form a Bidirectional Pathogenic Loop in SynucleinopathiesCell, 2011
- α-Synuclein and dopamine at the crossroads of Parkinson's diseaseTrends in Neurosciences, 2010
- Exogenous α-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cellsProceedings of the National Academy of Sciences of the United States of America, 2009
- Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synucleinProceedings of the National Academy of Sciences of the United States of America, 2009
- The new mutation, E46K, of α‐synuclein causes parkinson and Lewy body dementiaAnnals of Neurology, 2003