Mechanisms of Alpha-Synuclein Action on Neurotransmission: Cell-Autonomous and Non-Cell Autonomous Role

Emanuele, Marco; Chieregatti, Evelina

doi:10.3390/biom5020865

Cited by 41 publications

(31 citation statements)

References 206 publications

(230 reference statements)

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“…1B) is a short, 140-amino-acid protein (12) that exists at relatively high concentrations (∼50 μM) at neuronal synapses (13). This protein exists as an unstructured monomer in solution but will form an extended α-helix in the presence of cellular membranes or artificial lipids (14)(15)(16), where it can carry out its roles in vesicle trafficking and second-messenger release (17). During neurodegeneration in Parkinson's disease and other synucleinopathies, the protein will form β-sheet rich amyloid aggregates that are toxic to cells (18).…”

Section: Significancementioning

confidence: 99%

α-Synuclein O-GlcNAcylation alters aggregation and toxicity, revealing certain residues as potential inhibitors of Parkinson’s disease

Levine

Galesic

Balana

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

167

164

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A compelling link is emerging between the posttranslational modification O-GlcNAc and protein aggregation. A prime example is α-synuclein, which forms toxic aggregates that are associated with neurodegeneration in Parkinson’s and related diseases. α-Synuclein has been shown to be O-GlcNAcylated at nine different positions in in vivo proteomics experiments from mouse and human tissues. This raises the possibility that O-GlcNAc may alter the aggregation of this protein and could be both an important biological mediator of neurodegeneration and also a therapeutic target. Here, we expand upon our previous research in this area through the chemical synthesis of six site-specifically O-GlcNAcylated variants of α-synuclein. We then use a variety of biochemical experiments to show that O-GlcNAc in general inhibits the aggregation of α-synuclein but can also alter the structure of α-synuclein aggregates in site-specific ways. Additionally, an α-synuclein protein bearing three O-GlcNAc modifications can inhibit the aggregation of unmodified protein. Primary cell culture experiments also show that several of the O-GlcNAc sites inhibit the toxicity of extracellular α-synuclein fibers that are likely culprits in the spread of Parkinson’s disease. We also demonstrate that O-GlcNAcylation can inhibit the aggregation of an aggressive mutant of α-synuclein, indicating that therapies currently in development that increase this modification might be applied in animal models that rely on this mutant. Finally, we also show that the pan-selective antibody for O-GlcNAc does not generally recognize this modification on α-synuclein, potentially explaining why it remains understudied. These results support further development of O-GlcNAcylation tools and therapeutic strategies in neurodegenerative diseases.

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Section: Significancementioning

confidence: 99%

α-Synuclein O-GlcNAcylation alters aggregation and toxicity, revealing certain residues as potential inhibitors of Parkinson’s disease

Levine

Galesic

Balana

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

167

164

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“…aSyn is abundantly expressed in neurons 1 , and mostly localizes at synapses where it regulates presynaptic vesicles turnover 2 . aSyn is also a constituent of Lewy bodies and neurites 3 , also named Lewy pathology (LP), the hallmarks of a group of neurodegenerative diseases named synucleinopathies that comprise Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB) 4,5 .…”

mentioning

confidence: 99%

The expression level of alpha-synuclein in different neuronal populations is the primary determinant of its prion-like seeding

Courte

Bousset

Boxberg

et al. 2020

Sci Rep

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Alpha-synuclein (aSyn)-rich aggregates propagate in neuronal networks and compromise cellular homeostasis leading to synucleinopathies such as Parkinson's disease. Aggregated aSyn spread follows a conserved spatio-temporal pattern that is not solely dependent on connectivity. Hence, the differential tropism of aSyn-rich aggregates to distinct brain regions, or their ability to amplify within those regions, must contribute to this process. To better understand what underlies aSyn-rich aggregates distribution within the brain, we generated primary neuronal cultures from various brain regions of wild-type mice and mice expressing a reduced level of aSyn, and exposed them to fibrillar aSyn. We then assessed exogenous fibrillar aSyn uptake, endogenous aSyn seeding, and endogenous aSyn physiological expression levels. Despite a similar uptake of exogenous fibrils by neuronal cells from distinct brain regions, the seeded aggregation of endogenous aSyn differed greatly from one neuronal population to another. The different susceptibility of neuronal populations was linked to their aSyn expression level. Our data establish that endogenous aSyn expression level plays a key role in fibrillar aSyn prion-like seeding, supporting that endogenous aSyn expression level participates in selective regional brain vulnerability.

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“…12 When in contact with membranes, the protein forms an extended α -helix that can induce membrane bending, 13–15 while it exists as predominantly an unstructured monomer in solution and the cytosol. In PD and other synucleinopathies, however, α -synuclein is found in aggregates that have the features of the β -sheet rich fibers that are common to all amyloid proteins.…”

mentioning

confidence: 99%

O-GlcNAcylation of α-Synuclein at Serine 87 Reduces Aggregation without Affecting Membrane Binding

et al. 2017

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The aggregation of neurodegenerative-disease associated proteins can be affected by many factors, including a variety of post-translational modifications. One such modification, O-GlcNAcylation, has been found on some of these aggregation prone proteins, including α-synuclein, the major protein that plays a causative role in synucleinopathies like Parkinson’s disease. We previously used synthetic protein chemistry to prepare α-synuclein bearing a homogeneous O-GlcNAc modification at threonine 72 and showed that this modification inhibits protein aggregation. However, the effects of the other eight O-GlcNAcylation sites that have been identified were unknown. Here, we use a similar synthetic strategy to investigate the consequences of this modification at one of these sites, serine 87. We show that O-GlcNAcylation at this site also inhibits α-synuclein aggregation but to a lesser extent than that for the same modification at threonine 72. However, we also find that this modification does not affect the membrane-binding properties of α-synuclein, which differentiates it from phosphorylation at the same site. These results further support the development of therapies that can elevate O-GlcNAcylation of α-synuclein to slow the progression of Parkinson’s disease.

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Mechanisms of Alpha-Synuclein Action on Neurotransmission: Cell-Autonomous and Non-Cell Autonomous Role

Cited by 41 publications

References 206 publications

α-Synuclein O-GlcNAcylation alters aggregation and toxicity, revealing certain residues as potential inhibitors of Parkinson’s disease

α-Synuclein O-GlcNAcylation alters aggregation and toxicity, revealing certain residues as potential inhibitors of Parkinson’s disease

The expression level of alpha-synuclein in different neuronal populations is the primary determinant of its prion-like seeding

O-GlcNAcylation of α-Synuclein at Serine 87 Reduces Aggregation without Affecting Membrane Binding

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