α-Synuclein Induces the GSK-3-Mediated Phosphorylation and Degradation of NURR1 and Loss of Dopaminergic Hallmarks

Overview

Journal Mol Neurobiol

Specialties Molecular Biology
Neurology

Date 2021 Oct 5

PMID 34609698

Citations 4

Authors

Angel Juan Garcia-Yague

Isabel Lastres-Becker

Leonidas Stefanis

Demetrios K Vassilatis

Antonio Cuadrado

Affiliations

Soon will be listed here.

Abstract

In Parkinson's disease, the dysfunction of the dopaminergic nigrostriatal tract involves the loss of function of dopaminergic neurons of the substantia nigra pars compacta followed by death of these neurons. The functional recovery of these neurons requires a deep knowledge of the molecules that maintain the dopaminergic phenotype during adulthood and the mechanisms that subvert their activity. Previous studies have shown that transcription factor NURR1, involved in differentiation and maintenance of the dopaminergic phenotype, is downregulated by α-synuclein (α-SYN). In this study, we provide a mechanistic explanation to this finding by connecting α-SYN-induced activation of glycogen synthase kinase-3 (GSK-3) with NURR1 phosphorylation followed by proteasomal degradation. The use of sequential deletion mutants and single point mutants of NURR1 allowed the identification of a domain comprising amino acids 123-PSSPPTPSTPS-134 that is targeted by GSK-3 and leads to subsequent ubiquitination and proteasome degradation. This study provides a detailed analysis of the regulation of NURR1 stability by phosphorylation in synucleinopathies such as Parkinson's disease.

Citing Articles

Synaptic phosphoproteome modifications and cortical circuit dysfunction are linked to the early-stage progression of alpha-synuclein aggregation.

Dutta S, Hensel J, Scott A, Mohallem R, Rossitto L, Khan H bioRxiv. 2025; .

PMID: 39896549 PMC: 11785254. DOI: 10.1101/2025.01.24.634820.

Insulin Resistance Is a Modifying Factor for Parkinson's Disease.

Zagare A, Hemedan A, Almeida C, Frangenberg D, Gomez-Giro G, Antony P Mov Disord. 2024; 40(1):67-76.

PMID: 39499190 PMC: 11752983. DOI: 10.1002/mds.30039.

Mechanisms of NURR1 Regulation: Consequences for Its Biological Activity and Involvement in Pathology.

Garcia-Yague A, Cuadrado A Int J Mol Sci. 2023; 24(15).

PMID: 37569656 PMC: 10419244. DOI: 10.3390/ijms241512280.

Na,K-ATPase and Cardiotonic Steroids in Models of Dopaminergic System Pathologies.

Markina A, Kazanskaya R, Timoshina J, Zavialov V, Abaimov D, Volnova A Biomedicines. 2023; 11(7).

PMID: 37509460 PMC: 10377002. DOI: 10.3390/biomedicines11071820.

The Crucial Roles of Pitx3 in Midbrain Dopaminergic Neuron Development and Parkinson's Disease-Associated Neurodegeneration.

Wang X, Chen X, Liu G, Cai H, Le W Int J Mol Sci. 2023; 24(10).

PMID: 37239960 PMC: 10218497. DOI: 10.3390/ijms24108614.

References

Martinat C, Bacci J, Leete T, Kim J, Vanti W, Newman A . Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype. Proc Natl Acad Sci U S A. 2006; 103(8):2874-9. PMC: 1413837. DOI: 10.1073/pnas.0511153103. View

Jankovic J, Chen S, Le W . The role of Nurr1 in the development of dopaminergic neurons and Parkinson's disease. Prog Neurobiol. 2005; 77(1-2):128-38. DOI: 10.1016/j.pneurobio.2005.09.001. View

Decressac M, Volakakis N, Bjorklund A, Perlmann T . NURR1 in Parkinson disease--from pathogenesis to therapeutic potential. Nat Rev Neurol. 2013; 9(11):629-36. DOI: 10.1038/nrneurol.2013.209. View

Kadkhodaei B, Ito T, Joodmardi E, Mattsson B, Rouillard C, Carta M . Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. J Neurosci. 2009; 29(50):15923-32. PMC: 6666174. DOI: 10.1523/JNEUROSCI.3910-09.2009. View

Schimmel J, Crews L, Chikaraishi D . 4.5 kb of the rat tyrosine hydroxylase 5' flanking sequence directs tissue specific expression during development and contains consensus sites for multiple transcription factors. Brain Res Mol Brain Res. 2000; 74(1-2):1-14. DOI: 10.1016/s0169-328x(99)00234-x. View

Kim K, Kim C, Hwang D, Seo H, Chung S, Hong S . Orphan nuclear receptor Nurr1 directly transactivates the promoter activity of the tyrosine hydroxylase gene in a cell-specific manner. J Neurochem. 2003; 85(3):622-34. DOI: 10.1046/j.1471-4159.2003.01671.x. View

Sacchetti P, Mitchell T, Granneman J, Bannon M . Nurr1 enhances transcription of the human dopamine transporter gene through a novel mechanism. J Neurochem. 2001; 76(5):1565-72. DOI: 10.1046/j.1471-4159.2001.00181.x. View

Hermanson E, Joseph B, Castro D, Lindqvist E, Aarnisalo P, Wallen A . Nurr1 regulates dopamine synthesis and storage in MN9D dopamine cells. Exp Cell Res. 2003; 288(2):324-34. DOI: 10.1016/s0014-4827(03)00216-7. View

Hermanson E, Borgius L, Bergsland M, Joodmardi E, Perlmann T . Neuropilin1 is a direct downstream target of Nurr1 in the developing brain stem. J Neurochem. 2006; 97(5):1403-11. DOI: 10.1111/j.1471-4159.2006.03829.x. View

10.

Parkinson G, Dayas C, Smith D . Age-related gene expression changes in substantia nigra dopamine neurons of the rat. Mech Ageing Dev. 2015; 149:41-9. DOI: 10.1016/j.mad.2015.06.002. View

11.

Le W, Conneely O, Zou L, He Y, Saucedo-Cardenas O, Jankovic J . Selective agenesis of mesencephalic dopaminergic neurons in Nurr1-deficient mice. Exp Neurol. 1999; 159(2):451-8. DOI: 10.1006/exnr.1999.7191. View

12.

Zetterstrom R, Solomin L, Jansson L, Hoffer B, Olson L, Perlmann T . Dopamine neuron agenesis in Nurr1-deficient mice. Science. 1997; 276(5310):248-50. DOI: 10.1126/science.276.5310.248. View

13.

Xu P, Liang R, Jankovic J, Hunter C, Zeng Y, Ashizawa T . Association of homozygous 7048G7049 variant in the intron six of Nurr1 gene with Parkinson's disease. Neurology. 2002; 58(6):881-4. DOI: 10.1212/wnl.58.6.881. View

14.

Le W, Xu P, Jankovic J, Jiang H, Appel S, Smith R . Mutations in NR4A2 associated with familial Parkinson disease. Nat Genet. 2002; 33(1):85-9. DOI: 10.1038/ng1066. View

15.

Gomez-Benito M, Granado N, Garcia-Sanz P, Michel A, Dumoulin M, Moratalla R . Modeling Parkinson's Disease With the Alpha-Synuclein Protein. Front Pharmacol. 2020; 11:356. PMC: 7191035. DOI: 10.3389/fphar.2020.00356. View

16.

Olgiati S, Thomas A, Quadri M, Breedveld G, Graafland J, Eussen H . Early-onset parkinsonism caused by alpha-synuclein gene triplication: Clinical and genetic findings in a novel family. Parkinsonism Relat Disord. 2015; 21(8):981-6. DOI: 10.1016/j.parkreldis.2015.06.005. View

17.

Ahn T, Kim S, Kim J, Park S, Lee D, Min H . alpha-Synuclein gene duplication is present in sporadic Parkinson disease. Neurology. 2007; 70(1):43-9. DOI: 10.1212/01.wnl.0000271080.53272.c7. View

18.

Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg M . alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 2002; 4(2):160-4. DOI: 10.1038/ncb748. View

19.

Anderson J, Walker D, Goldstein J, de Laat R, Banducci K, Caccavello R . Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem. 2006; 281(40):29739-52. DOI: 10.1074/jbc.M600933200. View

20.

Lin X, Parisiadou L, Sgobio C, Liu G, Yu J, Sun L . Conditional expression of Parkinson's disease-related mutant α-synuclein in the midbrain dopaminergic neurons causes progressive neurodegeneration and degradation of transcription factor nuclear receptor related 1. J Neurosci. 2012; 32(27):9248-64. PMC: 3417246. DOI: 10.1523/JNEUROSCI.1731-12.2012. View