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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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α-syn and Macroautophagy. (A) Macroautophagy is composed of fine-tuned machinery that ensures specific target recognition and cargo delivery to the lysosome; (B) Accumulated α-syn increases mTor and decreases Atg7 levels, promoting mislocalization of Atg9 and leading to impairment of macroautophagy; (C) The α-syn familial mutation E46K can inhibit macroautophagy via JNK/Blc2, an mTor independent pathway; (D) On the other hand, two different effects are associated with the A53T α-syn mutation: an increase in mitophagy, and accumulation of autophagosomes due to impaired degradation; (E) α-syn aggregates cannot be degraded by macroautophagy, leading to the impairment of the pathway.
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biomolecules-05-00435-f002: α-syn and Macroautophagy. (A) Macroautophagy is composed of fine-tuned machinery that ensures specific target recognition and cargo delivery to the lysosome; (B) Accumulated α-syn increases mTor and decreases Atg7 levels, promoting mislocalization of Atg9 and leading to impairment of macroautophagy; (C) The α-syn familial mutation E46K can inhibit macroautophagy via JNK/Blc2, an mTor independent pathway; (D) On the other hand, two different effects are associated with the A53T α-syn mutation: an increase in mitophagy, and accumulation of autophagosomes due to impaired degradation; (E) α-syn aggregates cannot be degraded by macroautophagy, leading to the impairment of the pathway.

Mentions: Macroautophagy, commonly referred to as “autophagy”, is the most scrutinized and well known of the three autophagic mechanisms. This “content-blind” pathway relies on the formation of de novo double membrane-bound vesicles to sequester intracellular components, including whole organelles, towards the lysosome [110,111]. This membrane formation mainly relies on the autophagy related protein (Atg) 9, both in yeast and humans [112,113,114,115]. Macroautophagy is found constitutively active but further activation via the mTOR pathway, the mammalian target of rapamycin [116], or the PI3kinase/beclin/vsp34 pathway, also known as mTOR-independent pathway, is possible [117]. Autophagosome formation requires two ubiquitination steps highly regulated by Atg proteins [118,119,120]. Initially Atg12 is conjugated with Atg5, a process involving Atg7 and Atg10 [121,122]. The Atg12-Atg5 complex is later targeted to the autophagosome with Atg16 [123,124]. The second ubiquitination step requires Atg8 (also known by LC3). LC3 is C-terminally cleaved by Atg4 to form LC3-I [125,126], which is then conjugated to the lipid phosphatidylethanolamine (PE) by Atg7 and Atg3 to generate LC3-II [122,127]. Interestingly, the Atg12-Atg5 complex originated from first ubiquitination seems to be necessary for the LC3 processing and localization at the autophagosome membrane (Figure 2A) [128,129].


The Interplay between Alpha-Synuclein Clearance and Spreading.

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

α-syn and Macroautophagy. (A) Macroautophagy is composed of fine-tuned machinery that ensures specific target recognition and cargo delivery to the lysosome; (B) Accumulated α-syn increases mTor and decreases Atg7 levels, promoting mislocalization of Atg9 and leading to impairment of macroautophagy; (C) The α-syn familial mutation E46K can inhibit macroautophagy via JNK/Blc2, an mTor independent pathway; (D) On the other hand, two different effects are associated with the A53T α-syn mutation: an increase in mitophagy, and accumulation of autophagosomes due to impaired degradation; (E) α-syn aggregates cannot be degraded by macroautophagy, leading to the impairment of the pathway.
© Copyright Policy
Related In: Results  -  Collection

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

biomolecules-05-00435-f002: α-syn and Macroautophagy. (A) Macroautophagy is composed of fine-tuned machinery that ensures specific target recognition and cargo delivery to the lysosome; (B) Accumulated α-syn increases mTor and decreases Atg7 levels, promoting mislocalization of Atg9 and leading to impairment of macroautophagy; (C) The α-syn familial mutation E46K can inhibit macroautophagy via JNK/Blc2, an mTor independent pathway; (D) On the other hand, two different effects are associated with the A53T α-syn mutation: an increase in mitophagy, and accumulation of autophagosomes due to impaired degradation; (E) α-syn aggregates cannot be degraded by macroautophagy, leading to the impairment of the pathway.
Mentions: Macroautophagy, commonly referred to as “autophagy”, is the most scrutinized and well known of the three autophagic mechanisms. This “content-blind” pathway relies on the formation of de novo double membrane-bound vesicles to sequester intracellular components, including whole organelles, towards the lysosome [110,111]. This membrane formation mainly relies on the autophagy related protein (Atg) 9, both in yeast and humans [112,113,114,115]. Macroautophagy is found constitutively active but further activation via the mTOR pathway, the mammalian target of rapamycin [116], or the PI3kinase/beclin/vsp34 pathway, also known as mTOR-independent pathway, is possible [117]. Autophagosome formation requires two ubiquitination steps highly regulated by Atg proteins [118,119,120]. Initially Atg12 is conjugated with Atg5, a process involving Atg7 and Atg10 [121,122]. The Atg12-Atg5 complex is later targeted to the autophagosome with Atg16 [123,124]. The second ubiquitination step requires Atg8 (also known by LC3). LC3 is C-terminally cleaved by Atg4 to form LC3-I [125,126], which is then conjugated to the lipid phosphatidylethanolamine (PE) by Atg7 and Atg3 to generate LC3-II [122,127]. Interestingly, the Atg12-Atg5 complex originated from first ubiquitination seems to be necessary for the LC3 processing and localization at the autophagosome membrane (Figure 2A) [128,129].

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