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The Interplay between Alpha-Synuclein Clearance and Spreading.

Lopes da Fonseca T, Villar-Piqué A, Outeiro TF - Biomolecules (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

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Related in: MedlinePlus

Macrosecretion and lysosome-mediated exocytosis. (A) Since autophagosomes can be secreted to the extracellular space, it is possible that α-syn release occurs via this pathway, both in normal conditions and upon autophagosome accumulation due to lysosome impairment; (B) α-syn can alter the levels of important players in macroautophagy and eventually play a role in macrosecretion; (C) Lysosomes can fuse with the plasma membrane and release their content, a mechanism named lysosome exocytosis. The process is similar to the one observed in neurotransmitter release, α-syn may play a role; (D) Alternatively, impairment of protein degradation might promote the accumulation of high molecular weight species of α-syn inside the lysosome. One can speculate that, as observed in LSDs, the lysosomes might fuse with the plasma membrane and release α-syn oligomers and aggregates into the extracellular media and start the propagation of pathology.
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biomolecules-05-00435-f004: Macrosecretion and lysosome-mediated exocytosis. (A) Since autophagosomes can be secreted to the extracellular space, it is possible that α-syn release occurs via this pathway, both in normal conditions and upon autophagosome accumulation due to lysosome impairment; (B) α-syn can alter the levels of important players in macroautophagy and eventually play a role in macrosecretion; (C) Lysosomes can fuse with the plasma membrane and release their content, a mechanism named lysosome exocytosis. The process is similar to the one observed in neurotransmitter release, α-syn may play a role; (D) Alternatively, impairment of protein degradation might promote the accumulation of high molecular weight species of α-syn inside the lysosome. One can speculate that, as observed in LSDs, the lysosomes might fuse with the plasma membrane and release α-syn oligomers and aggregates into the extracellular media and start the propagation of pathology.

Mentions: No research has been done so far on the role of macrosecretion in either PD or other synucleinopathies but this pathway has already been linked to the intracellular accumulation of Abeta peptide upon autophagy impairment [238]. Thus, it would be very interesting to understand (1) what cellular inputs push the system towards one of the directions; (2) if α-syn can be secreted through this pathway; (3) if α-syn can also affect macrosecretion; and (4) if inflammation in PD is associated with the release of cytokines via macrosecretion (Figure 4A,B).


The Interplay between Alpha-Synuclein Clearance and Spreading.

Lopes da Fonseca T, Villar-Piqué A, Outeiro TF - Biomolecules (2015)

Macrosecretion and lysosome-mediated exocytosis. (A) Since autophagosomes can be secreted to the extracellular space, it is possible that α-syn release occurs via this pathway, both in normal conditions and upon autophagosome accumulation due to lysosome impairment; (B) α-syn can alter the levels of important players in macroautophagy and eventually play a role in macrosecretion; (C) Lysosomes can fuse with the plasma membrane and release their content, a mechanism named lysosome exocytosis. The process is similar to the one observed in neurotransmitter release, α-syn may play a role; (D) Alternatively, impairment of protein degradation might promote the accumulation of high molecular weight species of α-syn inside the lysosome. One can speculate that, as observed in LSDs, the lysosomes might fuse with the plasma membrane and release α-syn oligomers and aggregates into the extracellular media and start the propagation of pathology.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496680&req=5

biomolecules-05-00435-f004: Macrosecretion and lysosome-mediated exocytosis. (A) Since autophagosomes can be secreted to the extracellular space, it is possible that α-syn release occurs via this pathway, both in normal conditions and upon autophagosome accumulation due to lysosome impairment; (B) α-syn can alter the levels of important players in macroautophagy and eventually play a role in macrosecretion; (C) Lysosomes can fuse with the plasma membrane and release their content, a mechanism named lysosome exocytosis. The process is similar to the one observed in neurotransmitter release, α-syn may play a role; (D) Alternatively, impairment of protein degradation might promote the accumulation of high molecular weight species of α-syn inside the lysosome. One can speculate that, as observed in LSDs, the lysosomes might fuse with the plasma membrane and release α-syn oligomers and aggregates into the extracellular media and start the propagation of pathology.
Mentions: No research has been done so far on the role of macrosecretion in either PD or other synucleinopathies but this pathway has already been linked to the intracellular accumulation of Abeta peptide upon autophagy impairment [238]. Thus, it would be very interesting to understand (1) what cellular inputs push the system towards one of the directions; (2) if α-syn can be secreted through this pathway; (3) if α-syn can also affect macrosecretion; and (4) if inflammation in PD is associated with the release of cytokines via macrosecretion (Figure 4A,B).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

Show MeSH
Related in: MedlinePlus