Publicação
The interplay between alpha-Synuclein clearance and spreading
| Resumo: | 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 (alpha-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 alpha-syn pathology. The intracellular homeostasis of alpha-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 alpha-syn propagation to different brain areas and, ultimately, for the spreading of pathology and disease progression. Here, we review the interplay between alpha-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. |
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| Autores principais: | Lopes da Fonseca, Tomás |
| Outros Autores: | Villar-Pique, Anna; Outeiro, Tiago F |
| Assunto: | MIDBRAIN DOPAMINE NEURONS CATHEPSIN-B ACTIVITY CHAPERONE-MEDIATED AUTOPHAGY CEREBROSPINAL-FLUID CENTRAL-NERVOUS-SYSTEM FORMATION IN-VITRO LEWY BODY DEMENTIA N-TERMINAL ACETYLATION GENOME-WIDE ASSOCIATION SPORADIC PARKINSONS-DISEASE alpha-synuclein Parkinson’s Disease autophagy spreading prion |
| Ano: | 2015 |
| País: | Portugal |
| Tipo de documento: | recensão |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade Nova de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório Institucional da UNL |
| Resumo: | 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 (alpha-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 alpha-syn pathology. The intracellular homeostasis of alpha-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 alpha-syn propagation to different brain areas and, ultimately, for the spreading of pathology and disease progression. Here, we review the interplay between alpha-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. |
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