Alpha-synuclein (SNCA) polymorphisms exert protective effects on memory after mild traumatic brain injury

Abstract

Problems with attention and short-term learning and memory are commonly reported after mild traumatic brain injury (mTBI). Due to the known relationships between α-synuclein (SNCA), dopaminergic transmission, and neurologic deficits, we hypothesized that SNCA polymorphisms might be associated with cognitive outcome after mTBI. A cohort of 91 mTBI patients one month after injury and 86 healthy controls completed a series of cognitive tests assessing baseline intellectual function, attentional function, and memory, and was genotyped at 13 common single nucleotide polymorphisms (SNPs) in the SNCA gene. Significant differences in two memory measures (p = 0.001 and 0.002), but not baseline intellectual function or attentional function tasks, were found between the mTBI group and controls. A highly significant protective association between memory performance and SNCA promoter SNP rs1372525 was observed in the mTBI patients (p = 0.006 and 0.029 for the long and short delay conditions of the California Verbal Learning Tests, respectively), where the presence of at least one copy of the A (minor) allele was protective after mTBI. These results may help elucidate the pathophysiology of cognitive alterations after mTBI, and thus warrant further investigation.

Genetic Influences on Patient-Oriented Outcomes in Traumatic Brain Injury: A Living Systematic Review of Non-Apolipoprotein E Single-Nucleotide Polymorphisms

“…Fifty-four publications described prospective cohort studies 16 , 17 , 19–24 , 26 – 31 , 34 , 35 , 37 , 38 , 40–44 , 46 – 53 , 55 , 57–64 , 66 – 69 , 71 , 73–80 , 83 Fourteen studies were retrospective cohort studies on banked DNA samples 18 , 25 , 32 , 33 , 36 , 39 , 45 , 54 , 56 , 65 , 70 , 72 , 82 , 83 Study location also varied significantly, with the most commonly reported country of origin being the United States ( n = 43). Twenty-six studies included fewer than 100 patients 17 , 19 , 24 , 26 , 27 , 32 , 35 , 37 , 40 , 42–44 , 47 , 50–53 , 57 , 67–69 , 71 , 74 , 76 , 78 , 80 Seven studies were published conference abstracts. 25 , 44 , 62 , 66 , 74 , 76 , 78 The diversity and number of studies make it difficult to provide summary tables in the body of the article, and all of these data are therefore provided as Supplementary Materials.…”

“…Ten studies documented the relationship between various SNPs and nonglobal patient outcomes (i.e., neuropsychiatric, behavioral, and other). 57 , 60 , 66 , 67 , 69 , 71–73 , 82 , 83 The targets for these polymorphisms included: ACE, 57 various oxytocin SNPs, 66 PERIOD3, 67 ATP binding cassette, 60 nitric oxide synthase-3 (NOS3), 69 alpha synuclein (SNCA), 71 kidney and brain expressed protein (KIBRA), 72 BMX, 73 methyenetetrahydrofolate reductase (MTHFR), 82 and adenosine A1 receptor. 83 Full details can be found in Supplementary Appendix 9 .…”

“…[54][55] A further 21 studies reported on varied miscellaneous SNPs that did not fall into any of the previous groupings. [57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][80][81][82][83] Study design varied. Fifty-four publications described prospective cohort studies 16,17,[19][20][21][22][23][24][26][27][28][29][30][31]34,35,37,38,[40][41][42][43][44][46][47][48][49][50]…”

“…Fifty-four publications described prospective cohort studies 16,17,[19][20][21][22][23][24][26][27][28][29][30][31]34,35,37,38,[40][41][42][43][44][46][47][48][49][50][51][52][53]55,[57][58][59][60][61][62][63][64][66][67][68][69]71,[73][74][75][76][77][78][79][80]…”

Novel therapies for combating chronic neuropathological sequelae of TBI

“…Exposure to TBI is a risk factor for PD, with increased age at injury, loss of consciousness, and severity of TBI contributing to greater risk (Crane et al, 2016;Gardner et al, 2014;Jafari et al, 2013;Lee et al, 2015;Lee et al, 2013). Genetic factors also link TBI and PD -presence of α-synuclein polymorphisms and polymorphic mixed-dinucleotide repeats were associated with reduced PD risk and improved cognitive outcome after mild TBI exposure (Goldman et al, 2012;Shee et al, 2016). An important role for α-synuclein in formation of the soluble N-ethylmaleimidesensitive factor attachment protein receptor (SNARE) complex (Burre et al, 2010;Chandra et al, 2005) and regulation of presynaptic vesicular pools (Murphy et al, 2000) connects αsynuclein to neurotransmitter exocytosis, with implications for synaptic dysfunction related to dementia.…”