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SNAP25 Gene Polymorphisms Protect Against Parkinson’s Disease and Modulate Disease Severity in Patients

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Abstract

Parkinson’s disease (PD) is a α-synucleinopathy in which intracellular aggregates of α-synuclein (α-syn) result in neurodegeneration and in the impairment of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex-mediated release of neurotransmitters. SNAP25 is a SNARE complex component: its concentration is increased in the cerebrospinal fluid of PD patients and this is related to the severity of cognitive and motor symptoms. Five SNAP25 single-nucleotide polymorphisms (SNPs) that modulate gene expression and were described to play a role in neurologic conditions (rs363050, rs363039, rs363043, rs3746544, and rs1051312) were analyzed in a cohort of 412 sporadic Italian PD patients and 1103 healthy controls (HC) in order to identify possible correlation with the disease. The SNAP25 rs1051312 C allele and CC genotype confer protection against PD onset, in particular in males (p = 0.003, OR(95%CI) = 0.67(0.51–0.88)) (pc = 0.008, OR(95%CI) = 0.28(0.10–0.70)). Co-segregation analyses revealed that the rs1051312 effect was reinforced when present within the rs363043 C-rs3746544 T-rs1051312 C haplotype (p = 3.3 × 10−4, OR = 0.47, 95%CI = 0.31–0.72), once again in males. Finally, rs363039 influenced age at onset (p = 0.02) and MMSE (Mini-Mental State Examination) scores (p = 0.01). The SNAP25 SNPs analyzed herein modulate gene expression at different levels as they are involved in binding miRNA and transcription factors; this suggests a possible synergistic effect of SNAP25 SNPs in the pathogenesis of PD. A replication in a larger and independent sample will help to further explore this hypothesis.

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Funding

This work was supported by the National Institutes of Health [Ricerca Corrente 2015].

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Authors and Affiliations

  1. IRCCS Fondazione Don Carlo Gnocchi, Milano, Italy

    Cristina Agliardi, Franca Rosa Guerini, Milena Zanzottera, Cherubino Di Lorenzo, Raffaello Nemni & Mario Clerici

  2. Center for Parkinson’s Disease and Movement Disorders, Ospedale di Circolo e Fondazione Macchi, Varese, Italy

    Giulio Riboldazzi

  3. Parkinson’s disease and Movement Disorders Unit, IRCCS National Neurological Institute C. Mondino, Pavia, Italy

    Roberta Zangaglia & Brigida Minafra

  4. Neurology Unit-Varese, Insubria University Varese, Varese, Italy

    Andrea Sturchio

  5. Department of Medical-Surgical Sciences and Biotechnologies, University of Rome, Rome, Italy

    Carlo Casali

  6. Department of Pathophisiology and Transplantation, University of Milan, Milan, Italy

    Raffaello Nemni & Mario Clerici

Authors
  1. Cristina Agliardi
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  2. Franca Rosa Guerini
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  3. Milena Zanzottera
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  4. Giulio Riboldazzi
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  5. Roberta Zangaglia
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  7. Carlo Casali
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  8. Cherubino Di Lorenzo
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  9. Brigida Minafra
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  10. Raffaello Nemni
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  11. Mario Clerici
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Corresponding author

Correspondence to Cristina Agliardi.

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The Ethical Committees of the three institutions approved the study; all the participants gave informed consent.

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The authors declare that they have no conflict of interest.

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Agliardi, C., Guerini, F.R., Zanzottera, M. et al. SNAP25 Gene Polymorphisms Protect Against Parkinson’s Disease and Modulate Disease Severity in Patients. Mol Neurobiol 56, 4455–4463 (2019). https://doi.org/10.1007/s12035-018-1386-0

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  • DOI: https://doi.org/10.1007/s12035-018-1386-0

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