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The mechanistic role of alpha-synuclein in the nucleus: impaired nuclear function caused by familial Parkinson's disease SNCA mutations.

Publication ,  Journal Article
Chen, V; Moncalvo, M; Tringali, D; Tagliafierro, L; Shriskanda, A; Ilich, E; Dong, W; Kantor, B; Chiba-Falek, O
Published in: Hum Mol Genet
November 4, 2020

Alpha-synuclein SNCA has been implicated in the etiology of Parkinson's disease (PD); however, the normal function of alpha-synuclein protein and the pathway that mediates its pathogenic effect is yet to be discovered. We investigated the mechanistic role of SNCA in the nucleus utilizing isogenic human-induced pluripotent stem cells-derived neurons from PD patients with autosomal dominant mutations, A53T and SNCA-triplication, and their corresponding corrected lines by genome- and epigenome-editing. Comparisons of shape and integrity of the nuclear envelope and its resistance to stresses found that both mutations result in similar nuclear envelope perturbations that were reversed in the isogenic mutation-corrected cells. Further mechanistic studies showed that SNCA mutation has adverse effects on the nucleus by trapping Ras-related nuclear protein (RAN) and preventing it from transporting key nuclear proteins such as, DNMT3A, for maintaining normal nuclear function. For the first time, we proposed that α-syn interacts with RAN and normally functions in the nucleocytoplasmic transport while exerts its pathogenic effect by sequestering RAN. We suggest that defects in the nucleocytoplasmic transport components may be a general pathomechanistic driver of neurodegenerative diseases.

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Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

November 4, 2020

Volume

29

Issue

18

Start / End Page

3107 / 3121

Location

England

Related Subject Headings

  • alpha-Synuclein
  • Parkinson Disease
  • Neurons
  • Mutation
  • Induced Pluripotent Stem Cells
  • Humans
  • Genetics & Heredity
  • DNA Methyltransferase 3A
  • DNA (Cytosine-5-)-Methyltransferases
  • Cell Nucleus
 

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MLA
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Chen, V., Moncalvo, M., Tringali, D., Tagliafierro, L., Shriskanda, A., Ilich, E., … Chiba-Falek, O. (2020). The mechanistic role of alpha-synuclein in the nucleus: impaired nuclear function caused by familial Parkinson's disease SNCA mutations. Hum Mol Genet, 29(18), 3107–3121. https://doi.org/10.1093/hmg/ddaa183
Chen, Vivian, Malik Moncalvo, Dominic Tringali, Lidia Tagliafierro, Ahila Shriskanda, Ekaterina Ilich, Wendy Dong, Boris Kantor, and Ornit Chiba-Falek. “The mechanistic role of alpha-synuclein in the nucleus: impaired nuclear function caused by familial Parkinson's disease SNCA mutations.Hum Mol Genet 29, no. 18 (November 4, 2020): 3107–21. https://doi.org/10.1093/hmg/ddaa183.
Chen V, Moncalvo M, Tringali D, Tagliafierro L, Shriskanda A, Ilich E, et al. The mechanistic role of alpha-synuclein in the nucleus: impaired nuclear function caused by familial Parkinson's disease SNCA mutations. Hum Mol Genet. 2020 Nov 4;29(18):3107–21.
Chen, Vivian, et al. “The mechanistic role of alpha-synuclein in the nucleus: impaired nuclear function caused by familial Parkinson's disease SNCA mutations.Hum Mol Genet, vol. 29, no. 18, Nov. 2020, pp. 3107–21. Pubmed, doi:10.1093/hmg/ddaa183.
Chen V, Moncalvo M, Tringali D, Tagliafierro L, Shriskanda A, Ilich E, Dong W, Kantor B, Chiba-Falek O. The mechanistic role of alpha-synuclein in the nucleus: impaired nuclear function caused by familial Parkinson's disease SNCA mutations. Hum Mol Genet. 2020 Nov 4;29(18):3107–3121.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

November 4, 2020

Volume

29

Issue

18

Start / End Page

3107 / 3121

Location

England

Related Subject Headings

  • alpha-Synuclein
  • Parkinson Disease
  • Neurons
  • Mutation
  • Induced Pluripotent Stem Cells
  • Humans
  • Genetics & Heredity
  • DNA Methyltransferase 3A
  • DNA (Cytosine-5-)-Methyltransferases
  • Cell Nucleus