The SNARE complex plays a crucial role in the synaptic exocytosis of neurotransmitters, a process involved in the Alzheimer’s disease (AD), the most common form of dementia. SNAP-25, STX1a, and VAMP2 are the core proteins of the SNARE complex, and changes in protein level are suggested to contribute to cognitive impairment and neuropsychiatric disorders. Single nucleotide polymorphisms (SNPs) in SNARE complex genes were shown to be associated with different diseases and different cognitive impairments. Chi-square analysis was used to compare case-control difference of ApoE4, SNAP-25 rs363039, rs363043, rs363950, STX1a rs4717806, rs2293489, and VAMP2 26bp Ins/Del genotype distribution in 192 AD, 187 mild cognitive impairment (MCI), and 200 healthy controls (HC). Results of genotype and allelic distribution of SNAP-25 rs363050 showed that AA genotype (AD versus HC: p = 1.5×10–4; MCI versus HC: p = 8.7×10–3) as well as A allele (AD versus HC: p = 6.0×10–4; MCI versus HC: p = 5.7×10–3) are significantly more frequent in AD and MCI compared to HC. Genotype distribution of STX1a rs4717806 and rs2293489 resulted significantly different in AD compared to HC (p = 0.032 and p = 0.047, respectively). Moreover, distribution of the STX1a rs4717806 allele in SNAP-25 rs363050 AA carriers was significantly different between MCI and HC (p = 0.018). Notably, in MCI, visual selective attention impairment was associated with the STX1a rs4717806 AA (pc = 0.027) genotype as well as the SNAP-25/STX1a rs363050/rs4717806 AA/A (pc = 0.022) combination. These data suggest that SNPs in SNARE complex genes may interfere and/or modulate the activity of the SNARE complex resulting in impairments of neurotransmission that involve attention brain areas.
American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Association, Washington, DC.
2.
ForlenzaOV, DinizBS, StellaF, TeixeiraAL, GattazWF (2013) Mild cognitive impairment. Part 1: Clinical characteristics and predictors of dementia. Rev Bras Psiquiatr35, 178–185.
3.
JahnR, SüdhofTC (1999) Membrane fusion and exocytosis. Annu Rev Biochem68, 863–911.
4.
GoldbergA, CurtisCL, KleimJA (2015) Linking genes to neurological clinical practice: The genomic basis for neurorehabilitation. J Neurol Phys Ther39, 52–61.
5.
SüdhofTC, JahnR (1991) Proteins of synaptic vesicles involved in exocytosis and membrane recycling. Neuron6, 665–677.
6.
BraidaD, GueriniFR, PonzoniL, CorradiniI, De AstisS, PattiniL, BolognesiE, BenfanteR, FornasariD, ChiappediM, GhezzoA, ClericiM, MatteoliM, SalaM (2015) Association between SNAP-25 gene polymorphisms and cognition in autism: Functional consequences and potential therapeutic strategies. Transl Psychiatry5, e500.
7.
GossoMF, de GeusEJ, PoldermanTJ, BoomsmaDI, HeutinkP, PosthumaD (2008) Common variants underlying cognitive ability: Further evidence for association between the SNAP-25 gene and cognition using a family-based study in two independent Dutch cohorts. Genes Brain Behav7, 355–364.
8.
GueriniFR, AgliardiC, SironiM, ArosioB, CalabreseE, ZanzotteraM, BolognesiE, RicciC, CostaAS, GalimbertiD, GriffantiL, BianchiA, SavazziF, MariD, ScarpiniE, BaglioF, NemniR, ClericiM (2014) Possible association between SNAP-25 single nucleotide polymorphisms and alterations of categorical fluency and functional MRI parameters in Alzheimer’s disease. J Alzheimers Dis42, 1015–1028.
9.
LewisJL, DongM, EarlesCA, ChapmanER (2001) The transmembrane domain of syntaxin 1A is critical for cytoplasmic domain protein-protein interactions. J Biol Chem4, 15458–15465.
10.
NakamuraK, AnithaA, YamadaK, TsujiiM, IwayamaY, HattoriE, ToyotaT, SudaS, TakeiN, IwataY, SuzukiK, MatsuzakiH, KawaiM, SekineY, TsuchiyaKJ, SugiharaG, OuchiY, SugiyamaT, YoshikawaT, MoriN (2008) Genetic and expression analyses reveal elevated expression of syntaxin 1A (STX1A) in high functioning autism. Int J Neuropsychopharmacol11, 1073–1084.
11.
NakamuraK, IwataY, AnithaA, MiyachiT, ToyotaT, YamadaS, TsujiiM, TsuchiyaKJ, IwayamaY, YamadaK, HattoriE, MatsuzakiH, MatsumotoK, SuzukiK, SudaS, TakebayashiK, TakeiN, IchikawaH, SugiyamaT, YoshikawaT, MoriN (2011) Replication study of Japanese cohorts supports the role of STX1A in autism susceptibility. Prog Neuropsychopharmacol Biol Psychiatry35, 454–458.
12.
GaoQ, LiuL, ChenY, LiH, YangL, WangY, QianQ (2015) Synaptosome-related (SNARE) genes and their interactions contribute to the susceptibility and working memory of attention-deficit/hyperactivity disorder in males. Prog Neuropsychopharmacol Biol Psychiatry57, 132–139.
13.
DurdiakováJ, WarrierV, Banerjee-BasuS, Baron-CohenS, ChakrabartiB (2014) STX1A and Asperger syndrome: A replication study. Mol Autism5, 14.
14.
TropeanoM, Wöber-BingölC, KarwautzA, WagnerG, VassosE, Campos-de-SousaS, GraggaberA, ZeschHE, KienbacherC, NatriashviliS, KanburI, WöberC, CollierDA (2012) Association analysis of STX1A gene variants in common forms of migraine. Cephalalgia32, 203–212.
15.
KenarAN, AyOİ, HerkenH, ErdalME (2014) Association of VAMP-2 and Syntaxin 1A Genes with Adult Attention Deficit Hyperactivity Disorder. Psychiatry Investig11, 76–83.
16.
McKhannG, DrachmanD, FolsteinM, KatzmanR, PriceD, StadlanEM (1984) Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under theauspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology34, 939–944.
17.
PetersenRC (2004) Mild cognitive impairment as a diagnostic entity. J Intern Med256, 183–194.
18.
GrundmanM, PetersenRC, FerrisSH, ThomasRG, AisenPS, BennettDA, FosterNL, JackCRJr, GalaskoDR, DoodyR, KayeJ, SanoM, MohsR, GauthierS, KimHT, JinS, SchultzAN, SchaferK, MulnardR, van DyckCH, MintzerJ, ZamriniEY, Cahn-WeinerD, ThalLJ; Alzheimer’s Disease Cooperative Study (2004) Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials. Arch Neurol61, 59–66.
19.
LigthartGJ, CorberandJX, FournierC, GalanaudP, HijmansW, KennesB, Müller-HermelinkHK, SteinmannGG (1984) Admission criteria for immunogerontological studies in man: The SENIEUR protocol. Mech Ageing Dev28, 47–55.
20.
SpecialeL, CalabreseE, SaresellaM, TinelliC, MarianiC, SanvitoL, LonghiR, FerranteP (2007) Lymphocyte subset patterns and cytokine production in Alzheimer’s disease patients. Neurobiol Aging28, 1163–1169.
21.
MagniE, BinettiG, BianchettiA, RozziniR, TrabucchiM (1996) Mini-Mental State Examination: A normative study in Italian elderly population. Eur J Neurol3, 198–202.
22.
NovelliG, PapagnoC, CapitaniE, LaiaconaM, VallarG, CappaSF (1986) Tre test di ricerca e produzione lessicale: Taratura su soggetti normali. Arch Psicol Neurol Psichiatr47, 477–506.
23.
SpinnlerH, TognoniP (1987) Standardizzazione e taratura italiana di test neuropsicologici. Ital J Neurol Sci86, 1–20.
24.
BertolaniL, De RenziE, FaglioniP (1993) Test di memoria non verbale di impiego diagnostico in clinica: Taratura su soggetti normali. Arch Psicol Neurol Psichiatr54, 477–486.
FalboV, FloridiaG, GaudiS, ZoraqiG, TaruscioD (2002) A new polymorphism in the flanking region of human VAMP2 and hPer1 genes. Mol Cell Probes16, 391–392.
27.
BarrCL, FengY, WiggK, BloomS, RobertsW, MaloneM, SchacharR, TannockR, KennedyJL (2000) Identification of DNA variants in the SNAP-25 gene and linkage study of these polymorphisms and attention-deficit hyperactivity disorder. Mol Psychiatry5, 405–409.
28.
CaoL, WangF, YangQG, JiangW, WangC, ChenYP, ChenGH (2012) Reduced thyroid hormones with increased hippocampal SNAP-25 and Munc18-1 might involve cognitive impairment during aging. Behav Brain Res229, 131–7.
29.
Serrano-PozoA, FroschMP, MasliahE, HymanBT (2011) Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med1, a006189.
30.
Sánchez-MoraC, CormandB, Ramos-QuirogaJA, HervásA, BoschR, PalomarG, NogueiraM, Gómez-BarrosN, RicharteV, CorralesM, Garcia-MartinezI, CorominasR, GuijarroS, BigorraA, BayésM, CasasM, RibasésM (2013) Evaluation of common variants in 16 genes involved in the regulation of neurotransmitter release in ADHD. Eur Neuropsychopharmacol23, 426–35.
31.
CupertinoRB, SchuchJB, BandeiraCE, da SilvaBS, RovarisDL, KappelDB, ContiniV, Salatino-OliveiraA, VitolaES, KaramRG, HutzMH, RohdeLA, GrevetEH, BauCHD, MotaNR (2017) Replicated association of Synaptotagmin (SYT1) with ADHD and its broader influence in externalizing behaviors. Eur Neuropsychopharmacol27, 239–247.
32.
PerryRJ, HodgesJR (1999) Attention and executive deficits in Alzheimer’s disease. A critical review. Brain122, 383–404.
33.
ParasuramanR, GreenwoodP (2004) Visual attention, genetics and Alzheimer’s disease. In Vision in Alzheimer’s Disease,
Cronin-GolombA,
HofPR, eds. Karger Basel. Vol. 34. pp. 271–289.
34.
GreberS, LubecG, CairnsN, FountoulakisM (1999) Decreased levels of synaptosomal associated protein 25 in the brain of patients with Down syndrome and Alzheimer’s disease. Electrophoresis20, 928–934.
35.
Mukaetova-LadinskaEB, HurtJ, HonerWG, HarringtonCR, WischikCM (2002) Loss of synaptic but not cytoskeletal proteins in the cerebellum of chronic schizophrenics. Lett317, 161–165.
36.
Owe-LarssonB, BerglundM, KristenssonK, GaroffH, LarhammarD, BrodinL, LöwP (1999) Perturbation of the synaptic release machinery in hippocampal neurons by overexpression of SNAP-25 with the Semliki Forest virus vector. Eur J Neurosci11, 1981–1987.
