Regulation of alpha-synuclein expression by poly (ADP ribose) polymerase-1 (PARP-1) binding to the NACP-Rep1 polymorphic site upstream of the SNCA gene

Am J Hum Genet. 2005 Mar;76(3):478-92. doi: 10.1086/428655. Epub 2005 Jan 25.


Alleles at NACP-Rep1, the polymorphic microsatellite repeat located approximately 10 kb upstream of the alpha -synuclein gene (SNCA), are associated, in some reports, with differing risks of sporadic Parkinson disease (PD). We showed previously that NACP-Rep1 acts as a negative modulator of SNCA transcription, with an effect that varied threefold among different NACP-Rep1 alleles. Given that duplications and triplications of SNCA have been implicated in familial Parkinson disease (PD), even a 1.5-2-fold increase in alpha -synuclein expression may, over many decades, contribute to PD. Thus, the association of different NACP-Rep1 alleles with PD may be a consequence of polymorphic differences in transcriptional regulation of SNCA. Here we aimed to identify the factor(s) that bind to NACP-Rep1 and potentially contribute to SNCA transcriptional modulation, by pulling down proteins that bind to NACP-Rep1 and identifying them by mass spectrometry. One of these proteins was poly-(ADP-ribose) transferase/polymerase-1 (PARP-1), a DNA-binding protein and transcriptional regulator. Electrophoresis mobility shift and chromatin immunoprecipitation assays showed specific binding of PARP-1 to NACP-Rep1. Inhibition of PARP-1's catalytic domain increased the endogenous SNCA mRNA levels in cultured SH-SY5Y cells. Furthermore, PARP-1 binding to NACP-Rep1 specifically reduced the transcriptional activity of the SNCA promoter/enhancer in luciferase reporter assays. This down-regulation effect of PARP-1 depended on NACP-Rep1 being present in the construct and was abrogated by inhibiting PARP-1's catalytic activity with 3-aminobenzamide. The association of different NACP-Rep1 alleles with PD may be mediated, in part, by the effect of PARP-1, as well as other factors, on SNCA expression.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Base Sequence
  • Benzamides / pharmacology
  • Binding Sites / genetics
  • Cell Line
  • DNA / genetics
  • DNA / metabolism
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation
  • Humans
  • Microsatellite Repeats*
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Parkinson Disease / genetics
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Polymorphism, Genetic
  • Protein Binding
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Synucleins
  • alpha-Synuclein


  • Benzamides
  • Enzyme Inhibitors
  • Nerve Tissue Proteins
  • Poly(ADP-ribose) Polymerase Inhibitors
  • RNA, Messenger
  • SNCA protein, human
  • Synucleins
  • alpha-Synuclein
  • 3-aminobenzamide
  • DNA
  • Poly(ADP-ribose) Polymerases

Associated data

  • OMIM/163890
  • OMIM/168600