Does α-synuclein have a dual and opposing effect in preclinical vs. clinical Parkinson's disease?

Katerina Markopoulou, Joanna M. Biernacka, Sebastian M. Armasu, Kari J. Anderson, J. Eric Ahlskog, Bruce A Chase, Sun Ju Chung, Julie M. Cunningham, Matthew Farrer, Roberta Frigerio, Demetrius M. Maraganore

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

α-Synuclein gene (SNCA) multiplications cause familial parkinsonism and allele-length polymorphisms within the SNCA dinucleotide repeat REP1 increase the risk for developing Parkinson's disease (PD). Since SNCA multiplications increase SNCA expression, and REP1 genotypes that increase the risk of developing PD show increased SNCA expression in cell-culture systems, animal models, and human blood and brain, PD therapies seek to reduce SNCA expression. We conducted an observational study of 1098 PD cases to test the hypothesis that REP1 genotypes correlated with reduced SNCA expression are associated with better motor and cognitive outcomes. We evaluated the association of REP1 genotypes with survival free of Hoehn and Yahr stages 4 or 5 (motor outcome) and of Modified Telephone Interview for Cognitive Status score ≤27 or Alzheimer's Disease Dementia Screening Interview score ≥2 (cognitive outcome). Median disease duration at baseline was 3.3 years and median lag time from baseline to follow-up was 7.8 years. Paradoxically, REP1 genotypes associated with increased risk of developing PD and increased SNCA expression were associated with better motor (HR = 0.87, p = 0.046, covariate-adjusted age-scale analysis; HR = 0.85, p = 0.020, covariate-adjusted time-scale analysis) and cognitive outcomes (HR = 0.90, p = 0.12, covariate-adjusted age-scale analysis; HR = 0.85, p = 0.023, covariate-adjusted time-scale analysis). Our findings raise the possibility that SNCA has a dual, opposing, and time-dependent role. This may have implications for the development of therapies that target SNCA expression.

Original languageEnglish (US)
Pages (from-to)584-589
Number of pages6
JournalParkinsonism and Related Disorders
Volume20
Issue number6
DOIs
StatePublished - Jan 1 2014

Fingerprint

Synucleins
Parkinson Disease
Genotype
Alzheimer Disease
Interviews
Dinucleotide Repeats
Parkinsonian Disorders
Brain Diseases
Observational Studies
Animal Models
Cell Culture Techniques
Alleles
Survival
Therapeutics
Genes

Keywords

  • AD-8
  • Bp
  • H&Y
  • HR
  • LD
  • MEPD
  • MMSE
  • Outcomes
  • PD
  • Parkinson's disease
  • SNCA
  • SNP
  • TICS-M
  • UPDRS
  • α-Synuclein gene

ASJC Scopus subject areas

  • Neurology
  • Geriatrics and Gerontology
  • Clinical Neurology

Cite this

Markopoulou, K., Biernacka, J. M., Armasu, S. M., Anderson, K. J., Ahlskog, J. E., Chase, B. A., ... Maraganore, D. M. (2014). Does α-synuclein have a dual and opposing effect in preclinical vs. clinical Parkinson's disease? Parkinsonism and Related Disorders, 20(6), 584-589. https://doi.org/10.1016/j.parkreldis.2014.02.021

Does α-synuclein have a dual and opposing effect in preclinical vs. clinical Parkinson's disease? / Markopoulou, Katerina; Biernacka, Joanna M.; Armasu, Sebastian M.; Anderson, Kari J.; Ahlskog, J. Eric; Chase, Bruce A; Chung, Sun Ju; Cunningham, Julie M.; Farrer, Matthew; Frigerio, Roberta; Maraganore, Demetrius M.

In: Parkinsonism and Related Disorders, Vol. 20, No. 6, 01.01.2014, p. 584-589.

Research output: Contribution to journalArticle

Markopoulou, K, Biernacka, JM, Armasu, SM, Anderson, KJ, Ahlskog, JE, Chase, BA, Chung, SJ, Cunningham, JM, Farrer, M, Frigerio, R & Maraganore, DM 2014, 'Does α-synuclein have a dual and opposing effect in preclinical vs. clinical Parkinson's disease?', Parkinsonism and Related Disorders, vol. 20, no. 6, pp. 584-589. https://doi.org/10.1016/j.parkreldis.2014.02.021
Markopoulou, Katerina ; Biernacka, Joanna M. ; Armasu, Sebastian M. ; Anderson, Kari J. ; Ahlskog, J. Eric ; Chase, Bruce A ; Chung, Sun Ju ; Cunningham, Julie M. ; Farrer, Matthew ; Frigerio, Roberta ; Maraganore, Demetrius M. / Does α-synuclein have a dual and opposing effect in preclinical vs. clinical Parkinson's disease?. In: Parkinsonism and Related Disorders. 2014 ; Vol. 20, No. 6. pp. 584-589.
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