In vivo aggregation of presynaptic alpha-synuclein is not influenced by its phosphorylation at serine-129

Weston, Leah J.; Cook, Zoe T.; Stackhouse, Teresa L.; Sal, Mehtab K.; Schultz, Baergen I.; Tobias, Zachary J. C.; Osterberg, Valerie R.; Brockway, Nicole L; Pizano, Saheli; Glover, Greta; Weissman, Tamily A.; Unni, Vivek K.

doi:10.1016/j.nbd.2021.105291

Cited by 22 publications

(17 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, PLK2 inhibition reduced the RIPA-soluble fraction of pS129 and elevated the level of soluble α-syn, corroborating earlier data reported where PLK2 inhibition led to increased α-syn level by affecting transcription an/or autophagy [ 10 , 23 ]. Our data are in line with a recently published study using GFP-α-syn mice crossed with PLK2 knock-out mice and another study from the same group that opted for pharmacological inhibition of PLK2 in zebra fish, demonstrating that PLK2 deletion or inhibition had no influence on aggregate-formation even though they demonstrated a slight reduction in pS129 at the studied synaptic terminals [ 41 , 42 ].…”

Section: Discussionsupporting

confidence: 91%

Polo-like kinase 2 inhibition reduces serine-129 phosphorylation of physiological nuclear alpha-synuclein but not of the aggregated alpha-synuclein

et al. 2021

View full text Add to dashboard Cite

Accumulation of aggregated alpha-synuclein (α-syn) is believed to play a pivotal role in the pathophysiology of Parkinson’s disease (PD) and other synucleinopathies. As a key constituent of Lewy pathology, more than 90% of α-syn in Lewy bodies is phosphorylated at serine-129 (pS129) and hence, it is used extensively as a marker for α-syn pathology. However, the exact role of pS129 remains controversial and the kinase(s) responsible for the phosphorylation have yet to be determined. In this study, we investigated the effect of Polo-like kinase 2 (PLK2) inhibition on formation of pS129 using an ex vivo organotypic brain slice model of synucleinopathy. Our data demonstrated that PLK2 inhibition has no effect on α-syn aggregation, pS129 or inter-neuronal spreading of the aggregated α-syn seen in the organotypic slices. Instead, PLK2 inhibition reduced the soluble pS129 level in the nuclei. The same finding was replicated in an in vivo mouse model of templated α-syn aggregation and in human dopaminergic neurons, suggesting that PLK2 is more likely to be involved in S129-phosphorylation of the soluble physiological fraction of α-syn. We also demonstrated that reduction of nuclear pS129 following PLK2 inhibition for a short time before sample collection improves the signal-to-noise ratio when quantifying pS129 aggregate pathology.

show abstract

Section: Discussionsupporting

confidence: 91%

Polo-like kinase 2 inhibition reduces serine-129 phosphorylation of physiological nuclear alpha-synuclein but not of the aggregated alpha-synuclein

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Since the α-synuclein aggregation is considered as the main etiological factor in PD pathogenesis, and an acute exposure to neurotoxin cannot trigger the aggregation, attention is being given to the transgenic model of zebrafish (Chia et al, 2020). In some in vivo studies, the human α-synuclein protein is introduced with or without neurotoxins to the wild-type zebrafish to have a better representation of the PD pathogenesis (O'Donnell et al, 2014;Weston et al, 2021). More detailed discussions on the transgenic zebrafish model are discussed in the next section.…”

Section: Rotenonementioning

confidence: 99%

“…The advancement in genetic technology has enabled the construction of zebrafish transgenic models that express human wild-type α-synuclein protein (Prabhudesai et al, 2012;O'Donnell et al, 2014;Van Laar et al, 2020;Weston et al, 2021). Over-expression and aggregation of α-synuclein protein in zebrafish model of PD exhibited reduced mitochondrial activity and increased presence of reactive oxygen species (ROS), which led to neuronal apoptosis and cell death (O'Donnell et al, 2014;Robea et al, 2020).…”

Section: α-Synuclein (Snca) Genementioning

confidence: 99%

The Promise of the Zebrafish Model for Parkinson’s Disease: Today’s Science and Tomorrow’s Treatment

et al. 2021

View full text Add to dashboard Cite

The second most prevalent neurodegenerative disorder in the elderly is Parkinson’s disease (PD). Its etiology is unclear and there are no available disease-modifying medicines. Therefore, more evidence is required concerning its pathogenesis. The use of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is the basis of most animal models of PD. MPTP is metabolized by monoamine oxidase B (MAO B) to MPP + and induces the loss of dopaminergic neurons in the substantia nigra in mammals. Zebrafish have been commonly used in developmental biology as a model organism, but owing to its perfect mix of properties, it is now emerging as a model for human diseases. Zebrafish (Danio rerio) are cheap and easy to sustain, evolve rapidly, breed transparent embryos in large amounts, and are readily manipulated by different methods, particularly genetic ones. Furthermore, zebrafish are vertebrate species and mammalian findings obtained from zebrafish may be more applicable than those derived from genetic models of invertebrates such as Drosophila melanogaster and Caenorhabditis elegans. The resemblance cannot be taken for granted, however. The goal of the present review article is to highlight the promise of zebrafish as a PD animal model. As its aminergic structures, MPTP mode of action, and PINK1 roles mimic those of mammalians, zebrafish seems to be a viable model for studying PD. The roles of zebrafish MAO, however, vary from those of the two types of MAO present in mammals. The benefits unique to zebrafish, such as the ability to perform large-scale genetic or drug screens, should be exploited in future experiments utilizing zebrafish PD models.

show abstract

“…Screening of siRNA libraries implicated the role of the SphK1 gene in the possible phosphorylation of ASN on Ser129 [150]. ASN phosphorylated on this residue occurs in synucleinopathy lesions [151], but its requisite role in the ASN aggregation process is still debated and may even be a signal for degradation [152,153].…”

Section: The Relationship Between Asn Toxicity and Alteration Of S1p And Ceramide Signalingmentioning

confidence: 99%

Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease

Motyl

Strosznajder

Wencel

et al. 2021

IJMS

View full text Add to dashboard Cite

Molecular studies have provided increasing evidence that Parkinson’s disease (PD) is a protein conformational disease, where the spread of alpha-synuclein (ASN) pathology along the neuraxis correlates with clinical disease outcome. Pathogenic forms of ASN evoke oxidative stress (OS), neuroinflammation, and protein alterations in neighboring cells, thereby intensifying ASN toxicity, neurodegeneration, and neuronal death. A number of evidence suggest that homeostasis between bioactive sphingolipids with opposing function—e.g., sphingosine-1-phosphate (S1P) and ceramide—is essential in pro-survival signaling and cell defense against OS. In contrast, imbalance of the “sphingolipid biostat” favoring pro-oxidative/pro-apoptotic ceramide-mediated changes have been indicated in PD and other neurodegenerative disorders. Therefore, we focused on the role of sphingolipid alterations in ASN burden, as well as in a vast range of its neurotoxic effects. Sphingolipid homeostasis is principally directed by sphingosine kinases (SphKs), which synthesize S1P—a potent lipid mediator regulating cell fate and inflammatory response—making SphK/S1P signaling an essential pharmacological target. A growing number of studies have shown that S1P receptor modulators, and agonists are promising protectants in several neurological diseases. This review demonstrates the relationship between ASN toxicity and alteration of SphK-dependent S1P signaling in OS, neuroinflammation, and neuronal death. Moreover, we discuss the S1P receptor-mediated pathways as a novel promising therapeutic approach in PD.

show abstract

In vivo aggregation of presynaptic alpha-synuclein is not influenced by its phosphorylation at serine-129

Cited by 22 publications

References 82 publications

Polo-like kinase 2 inhibition reduces serine-129 phosphorylation of physiological nuclear alpha-synuclein but not of the aggregated alpha-synuclein

Polo-like kinase 2 inhibition reduces serine-129 phosphorylation of physiological nuclear alpha-synuclein but not of the aggregated alpha-synuclein

The Promise of the Zebrafish Model for Parkinson’s Disease: Today’s Science and Tomorrow’s Treatment

Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease

Contact Info

Product

Resources

About