title: The Interplay between Alpha-Synuclein Clearance and Spreading.
abstract: Parkinson's Disease (PD) is a complex neurodegenerative disorder classically characterized by movement impairment. Pathologically, the most striking features of PD are the loss of dopaminergic neurons and the presence of intraneuronal protein inclusions primarily composed of alpha-synuclein (α-syn) that are known as Lewy bodies and Lewy neurites in surviving neurons. Though the mechanisms underlying the progression of PD pathology are unclear, accumulating evidence suggests a prion-like spreading of α-syn pathology. The intracellular homeostasis of α-syn requires the proper degradation of the protein by three mechanisms: chaperone-mediated autophagy, macroautophagy and ubiquitin-proteasome. Impairment of these pathways might drive the system towards an alternative clearance mechanism that could involve its release from the cell. This increased release to the extracellular space could be the basis for α-syn propagation to different brain areas and, ultimately, for the spreading of pathology and disease progression. Here, we review the interplay between α-syn degradation pathways and its intercellular spreading. The understanding of this interplay is indispensable for obtaining a better knowledge of the molecular basis of PD and, consequently, for the design of novel avenues for therapeutic intervention.
authors: Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen 37073, Germany. tlopesdafonseca@gmail.com.|Instituto de Fisiologia, Faculty of Medicine, University of Lisbon, Lisboa 1649-028, Portugal. tlopesdafonseca@gmail.com.
authors: Tomás
authors: T
authors: Lopes da Fonseca
authors: Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen 37073, Germany. avillar@gwdg.de.
authors: Anna
authors: A
authors: Villar-Piqué
authors: Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen 37073, Germany. touteir@gwdg.de.|Instituto de Fisiologia, Faculty of Medicine, University of Lisbon, Lisboa 1649-028, Portugal. touteir@gwdg.de.|CEDOC, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa 1150, Portugal. touteir@gwdg.de.
authors: Tiago Fleming
authors: TF
authors: Outeiro
mesh_terms: D000818:Animals; D001343:Autophagy; D006801:Humans; D010300:Parkinson Disease / Q000378:metabolism*; D059748:Proteolysis; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein