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The Interplay between Alpha-Synuclein Clearance and Spreading

Lookup NU author(s): Professor Tiago OuteiroORCiD


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© 2015 by the authors; licensee MDPI, Basel, Switzerland.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.

Publication metadata

Author(s): da Fonseca TL, Villar-Piqué A, Outeiro TF

Publication type: Review

Publication status: Published

Journal: Biomolecules

Year: 2015

Volume: 5

Issue: 2

Pages: 435-471

Online publication date: 14/04/2015

Acceptance date: 07/04/2015

ISSN (print): 2218-273X

Publisher: MDPI AG

URL: .https//

DOI: 10.3390/biom5020435

PubMed id: 25874605