Abstract Details

Title Genetic Evidence for a Dual and Opposing Effect of alpha-Synuclein Expression in Preclinical Versus Clinical Parkinson's Disease

Topic Movement Disorders

Presentation(s) P05 - (-)

Poster/Presentation
Number 059

Objective

Background BACKGROUND: a-Synuclein (SNCA) gene overexpression is a cause of familial Parkinson's disease (PD). In sporadic PD, allele-length polymorphisms of the dinucleotide repeat sequence ("REP1") in the SNCA promoter confer PD susceptibility; longer alleles (263 bp) are associated with increased risk and increased expression, while shorter alleles (259 bp) with reduced risk and reduced expression (compared to the wild-type allele, 261 bp). Based on those observations, therapies to reduce SNCA expression in PD are under development. However, it is unknown whether reduced expression is associated with better outcomes.

Design/Methods DESIGN/METHODS: We conducted an observational study of 1,098 PD cases. SNCA REP1 genotypes were determined by sequencing. Outcomes were measured via telephone-interview. We studied the association of SNCA REP1 and survival free of motor (H&Y stages 4-5) and cognitive (TICS-M score ?27, or AD-8 score ?2 if incapacitated or deceased) outcomes via Cox proportional hazard models.

Results RESULTS: PD cases had a median 3.3 years motor-symptom duration at baseline, and were telephone-interviewed after a median 7.8 years (range, 3.3-13 years; median 11.1 years motor-symptom duration at follow-up). The reduced-expression SNCA REP1 259 bp allele was associated with worse motor and cognitive outcomes (motor: HR=1.23, 95% CI 1.04-1.47, P=0.02; cognitive: HR=1.23, 95% CI 1.05-1.45, P=0.01).

Conclusions CONCLUSIONS: Whereas reduced-expression SNCA genotypes have been shown to be associated with reduced PD susceptibility, we observed that these genotypes are also associated with worse motor and cognitive outcomes. Our results raise the possibility of a dual and opposing role of SNCA expression in pre-clinical versus clinical PD ("Janus effect"). This raises concerns about the efficacy and safety of therapies aiming to reduce SNCA expression in PD.

Authors/Disclosures
Katerina Markopoulou, MD, PhD (NorthShore University Health System) PRESENTER	Dr. Markopoulou has nothing to disclose.
J. E. Ahlskog, MD, PhD (Mayo Clinic)	Dr. Ahlskog has received publishing royalties from a publication relating to health care.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Sun Ju Chung, MD, PhD, FAAN (Neurology, Asan Medical Center)	Dr. Chung has nothing to disclose.
	No disclosure on file
Roberta Frigerio, MD (NorthShore University HealthSystem)	Dr. Frigerio has nothing to disclose.
Demetrius M. Maraganore, MD, FAAN (Tulane University School of Medicine)	Dr. Maraganore has nothing to disclose.
Francesco Muntoni, MD (UCL Institute of Child Health)	Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pfizer. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sarepta. Dr. Muntoni has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Biogen. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Dr. Muntoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. The institution of Dr. Muntoni has received research support from European Commission. The institution of Dr. Muntoni has received research support from Medical Research Council. The institution of Dr. Muntoni has received research support from Biogen. The institution of Dr. Muntoni has received research support from Muscular Dystrophy UK. The institution of Dr. Muntoni has received research support from MDA USA. The institution of Dr. Muntoni has received research support from Sarepta. The institution of Dr. Muntoni has received research support from Association Francoise Myopathies. Dr. Muntoni has received personal compensation in the range of $0-$499 for serving as a Clinical expert with UK NICE Committee.

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