α-Synuclein Translocates to the Nucleus to Activate Retinoic-Acid-Dependent Gene Transcription

Davidi, Dana; Schechter, Meir; Elhadi, Suaad Abd; Matatov, Adar; Nathanson, Lubov; Sharon, Ronit

doi:10.1016/j.isci.2020.100910

Cited by 51 publications

(77 citation statements)

References 81 publications

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“…However, the mechanism of action of α-syn in HD has not yet been determined and therefore, the connection between α-syn, CK2α’ and HD transcriptional deficits is new. α-Syn is primarily in the cytosol and interacts with cell membranes, but it has been reported to regulate gene expression (Decressac et al 2012, Davidi et al 2020). Specifically, phosphorylated forms of α-syn associated with α-syn aggregation have been seen to localize in the nucleus, where it could interfere with transcription (Fujiwara et al 2002, Schell et al 2009, Schaser et al 2019).…”

Section: Resultsmentioning

confidence: 99%

“…Our data strongly suggested a potential role of CK2α’ in regulating α-syn function. Although α-syn is not a transcription factor, several reports have shown the ability of α-syn to modulate the expression of other transcription factors such as Nurr1, which is involved in the regulation of inflammation and is differentially expressed between zQ175 and zQ175:CK2α’ (+/-) mice (Davidi et al 2020, Decressac et al 2012). α-syn also regulates the activation of NF-kβ by regulating MAPKs (Hoenen et al 2016).…”

Section: Discussionmentioning

confidence: 99%

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CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington’s disease

Zarate

Cuccu

et al. 2020

Preprint

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Huntington′s Disease (HD) is a neurodegenerative disorder caused a polyglutamine expansion in the HTT protein. This mutation causes HTT misfolding and aggregation, preferentially affecting neurons of the basal ganglia. Other aggregation-prone proteins like alpha-synuclein (α-syn), mostly associated with Parkinson′s disease (PD), has recently been involved in motor deficits in HD, but its mechanism of action is unknown. Here we showed that α-syn serine 129 phosphorylation (α-syn-pS129), a posttranslational modification linked to α-synucleinopathy, is highly phosphorylated in the brain of symptomatic zQ175 HD mice. We demonstrated that such phosphorylation is mediated by Protein Kinase CK2 alpha prime (CK2α′), which is preferentially induced in striatal neurons in HD. Knocking out one allele of CK2α′ in zQ175 mice decreased α-syn-pS129 in the striatum and ameliorated several HD-like symptoms including neuroinflammation, transcriptional alterations, excitatory synaptic transmission dysfunction and motor deficits. Our data suggests CK2α′-mediated synucleinopathy as a key molecular mechanism for striatal neurons degeneration in HD.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington’s disease

Zarate

Cuccu

et al. 2020

Preprint

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“…Adequate measures were taken to minimize pain and suffering. Cells HEK 293T, HeLa, SH-SY5Y and an inducible α-Syn-expressing SH-SY5Y cell line (48) were maintained in Dulbecco's modified eagle's medium (DMEM) supplemented with 10% FBS; 2% Lglutamine; 1% penicillin/streptomycin, sodiumpyruvate and non-essential amino acids (Biological Industries, Beit-Haemek, Israel). α-Syn expression was induced in the inducible SH-SY5Y cell line with 1 g/ml doxycycline (Dox, Sigma-Aldrich, Rehovot, Israel).…”

Section: Micementioning

confidence: 99%

α-Synuclein facilitates endocytosis by elevating the steady-state levels of phosphatidylinositol 4,5-bisphosphate

Schechter¹,

Atias

Elhadi³

et al. 2020

Journal of Biological Chemistry

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α-Synuclein (α-Syn) is a protein implicated in the pathogenesis of Parkinson’s disease (PD). It is an intrinsically disordered protein that binds acidic phospholipids. Growing evidence supports a role for α-Syn in membrane trafficking, including, mechanisms of endocytosis and exocytosis, although the exact role of α-Syn in these mechanisms is currently unclear. Here we investigate the associations of α-Syn with the acidic phosphoinositides (PIPs), phosphatidylinositol 4,5-bisphosphate (PI4,5P2) and phosphatidylinositol 3,4-bisphosphate (PI3,4P2). Our results show that α-Syn colocalizes with PIP2 and the phosphorylated active form of the clathrin adaptor protein 2 (AP2) at clathrin-coated pits. Using endocytosis of transferrin as an indicator for clathrin mediated endocytosis (CME), we find that α-Syn involvement in endocytosis is specifically mediated through PI4,5P2 levels on the plasma membrane. In accord with their effects on PI4,5P2 levels, the PD associated A30P, E46K and A53T mutations in α-Syn further enhance CME in neuronal and non-neuronal cells. However, Lysine to Glutamic acid substitutions at the KTKEGV repeat domain of α-Syn, that interfere with phospholipid binding, are ineffective in enhancing CME. We further show that the rate of synaptic vesicle (SV) endocytosis is differentially affected by the α-Syn mutations and associates with their effects on PI4,5P2 levels, however, with the exception of the A30P mutation. This study provides evidence for a critical involvement of PIPs in α-Syn-mediated membrane trafficking.

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“…4g). To find out whether Nir2 expression is required for α-Syn-mediated increases in PI4,5P 2 levels, we utilized SH-SY5Y cells, that inducibly express α-Syn under a Tet-On control [46]. Cells were infected to silence NIR2 expression using a viral vector expressing shNIR2.…”

Section: The Regulatory Role Of α-Syn On Pi45p 2 Levels Is Nir2depenmentioning

confidence: 99%

A role for α-Synuclein in axon growth and its implications in corticostriatal glutamatergic plasticity in Parkinson’s disease

Schechter¹,

Grigoletto

Abd-Elhadi

et al. 2020

Mol Neurodegeneration

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Background: α-Synuclein (α-Syn) is a protein implicated in the pathogenesis of Parkinson's disease (PD). α-Syn has been shown to associate with membranes and bind acidic phospholipids. However, the physiological importance of these associations to the integrity of axons is not fully clear.Methods: Biochemical, immunohistochemical and ultrastructural analyses in cultured neurons, transgenic mouse brains, PD and control human brains. Results:We analyzed the ultrastructure of cross-sectioned axons localized to white matter tracts (WMTs), within the dorsal striatum of old and symptomatic α-Syn transgenic mouse brains. The analysis indicated a higher density of axons of thinner diameter. Our findings in cultured cortical neurons indicate a role for α-Syn in elongation of the main axon and its collaterals, resulting in enhanced axonal arborization. We show that α-Syn effect to enhance axonal outgrowth is mediated through its activity to regulate membrane levels of the acidic phosphatidylinositol 4, 5-bisphosphate (PI4,5P 2 ). Moreover, our findings link α-Synenhanced axonal growth with evidence for axonal injury. In relevance to disease mechanisms, we detect in human brains evidence for a higher degree of corticostriatal glutamatergic plasticity within WMTs at early stages of PD. However, at later PD stages, the respective WMTs in the caudate are degenerated with accumulation of Lewy pathology. Conclusions:Our results show that through regulating PI4,5P 2 levels, α-Syn acts to elongate the main axon and collaterals, resulting in a higher density of axons in the striatal WMTs. Based on these results we suggest a role for α-Syn in compensating mechanisms, involving corticostriatal glutamatergic plasticity, taking place early in PD.

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α-Synuclein Translocates to the Nucleus to Activate Retinoic-Acid-Dependent Gene Transcription

Abstract: HIGHLIGHTS a-Syn normally binds RA and translocates to the nucleus to regulate transcription Nuclear translocation of a-Syn is regulated by calreticulin and Ca 2+ Nuclear translocation of a-Syn is linked to PD

Cited by 51 publications

References 81 publications

CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington’s disease

CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington’s disease

α-Synuclein facilitates endocytosis by elevating the steady-state levels of phosphatidylinositol 4,5-bisphosphate

A role for α-Synuclein in axon growth and its implications in corticostriatal glutamatergic plasticity in Parkinson’s disease

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