Neurol Sci (2010) 31:741–749 DOI 10.1007/s10072-010-0400-8
ORIGINAL ARTICLE
Serotonin transporter and saitohin genes in risk of Alzheimer’s disease and frontotemporal lobar dementia: preliminary findings Cristina Lorenzi • Alessandra Marcone • Adele Pirovano • Elena Marino • Francesco Cordici • Chiara Cerami • Dario Delmonte • Stefano F. Cappa • Placido Bramanti • Enrico Smeraldi
Received: 23 July 2009 / Accepted: 26 August 2010 / Published online: 18 September 2010 Ó Springer-Verlag 2010
Abstract Serotonergic transmission impairment and abnormal phosphorylation of tau protein have been implicated in the physiopathology of Alzheimer’s disease (AD) and frontotemporal lobar dementia (FTLD). Associations between a functional polymorphism (5-HTTLPR), in the promoter region of the serotonin transporter gene, and susceptibility to sporadic AD and FTLD have been reported. A polymorphism (Q7R) in saitohin gene inside the microtubule-associated protein tau gene has also been related to dementia. To determine the possible role of the two polymorphisms in susceptibility to AD and FTLD, we performed a case–control study collecting 218 Italian sporadic dementia patients and 54 controls. We found a significant excess of 5-HTTLPR short alleles and an interaction between 5-HTTLPR and Q7R polymorphisms in demented subjects. Our study confirms the role of 5-HTTLPR as a potential susceptibility factor for sporadic dementia in the Italian population, and suggests a possible C. Lorenzi (&) A. Pirovano E. Marino D. Delmonte Clinical Neurosciences Department, San Raffaele Turro Hospital, Vita-Salute San Raffaele University, via Stamira D’Ancona 20, 20127 Milan, Italy e-mail:
[email protected] A. Marcone C. Cerami Clinical Neurosciences Department, San Raffaele Turro Hospital, San Raffaele Scientific Institute, via Stamira D’Ancona 20, 20127 Milan, Italy F. Cordici P. Bramanti IRCCS Centro Neurolesi ‘‘Bonino Pulejo’’, Messina, Italy S. F. Cappa E. Smeraldi Clinical Neurosciences Department, San Raffaele Turro Hospital, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, via Stamira D’Ancona 20, 20127 Milan, Italy
interaction between 5-HTTLPR and Q7R polymorphisms in neurodegenerative diseases. Keywords Dementia Serotonin transporter Saitohin Serotonin Case–control study Genetics
Introduction Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders characterized by cognitive decline and behavioral–psychological symptoms. AD is the most frequent type of dementia, increasing in prevalence with age up to more than 40% above age 85. It is characterized by insidious onset and gradual progression; the initial phase of the disease is marked by deficit of episodic memory, while other impairments (naming, executive function and visuospatial abilities) may be subtle or entirely absent [1]. FTLD is considered to be one of the most common neurodegenerative dementia syndromes after AD and affects people in middle age, accounting for up to 20% of presenile dementia cases [2]. FTLD constitutes the group of lobar neurodegenerative diseases with mean onset at age 52, involving the frontal and temporal lobes. Frontal FTLD is characterized by early behavioral disorders and executive dysfunction. With disease’s progression, the impairment spreads to most cognitive domains; however, at early stages, FTLD patients tend to be less impaired than AD patients on some tests of memory, while they show significantly greater impairment on executive tasks [1]. Clinical studies, comparing AD and FTLD, highlighted distinctive clinical pictures, reflecting the distribution of
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brain degeneration: in AD patients, the course of cognitive difficulties indicates the spreading of cortical damage from the peri-hippocampal regions to the posterior associative areas, while in FTLD pathological changes in the orbitofrontal and dorsolateral prefrontal cortex (DLPFC) are reported [3]. Nevertheless, an increasing number of studies indicate biochemical pathways in common to AD and FTLD, leading to cognitive impairments with a possible shared genetic background [4]. One of these biochemical pathways could be the Reelinsignal transduction cascade, which is activated by apolipoprotein E and shows, as ending point, the phosphorylation of tau, a protein originally identified as a microtubule-associated protein tau (MAPT) and able to regulate microtubule assembly and stability [4]. Importantly, hyperphosphorylated tau comprises the paired helical filament, whose pathological deposition as neurofibrillary tangles is implicated in AD and in the pathogenesis of other neurodegenerative disorders, such as FTLD [5]. In this view, AD and FTLD may be considered secondary tauopathies, because, even if tau is probably not the initial pathological factor, tau aggregates contribute to the final Central Nervous System (CNS) degeneration [6–13]. From genetic point of view, besides the bases of early-onset AD (EOAD), affecting about 5–10% of the population, are relatively well characterized [14, 15], the pathogenesis of the more common late-onset AD (LOAD) is still highly debated [15]. Like AD, FTLD shows both autosomal dominant and sporadic genetic model. Even if less than 10% FTLD cases show an autosomal dominant inheritance pattern, up to 40% of FTLD patients have some familiar history of dementia and/or neuropsychiatric disorders [16]. Since many studies reported MAPT mutations also in dementia patients, lacking documented positive family history [17–20], it remains to be seen if one can generalize genetic bases to all FTLD or AD cases, both familial and sporadic forms. Moreover, other than poorly documented family histories, in case of dementias, there is also the matter of incomplete penetrance of MAPT gene mutations or the occurrence of de novo mutations in other genes [21]. Given this complex pattern, many studies focused on a plenty of polymorphic genes, other than MAPT, demonstrating interesting, even if highly heterogeneous evidences, about genetic susceptibility to sporadic AD and FTLD [15, 16]. Among possible candidate genes, the serotonin transporter (5-HTT) is under discussion as a potential genetic risk factor for dementia. Extensive data from postmortem and biopsy studies implicate a deficit in serotonergic neurotransmission,
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showing serotonin neuron and neurotransmitter loss in AD. Serotonin (5-hydroxytryptamine or 5-HT) is a key neurotransmitter in the central and peripheral nervous system and plays a relevant role in behavior and cognitive traits, like mood, learning and memory functions, impaired in neuropsychiatric disorders related to old age. Serotonergic pathways have also been involved in the pathogenesis of depression, agitation and psychotic symptom in AD [22]. For instance, reduction of 5-HT and its metabolites has been reported in AD brains [23]. Moreover, a decrease in the number of serotonin transporter (5-HTT) reuptake sites in several brain regions [24] and platelets of patients with LOAD have been reported [25]. A polymorphism of the serotonin transporter gene (5-HTT), also called 5-HTTLPR, has been investigated as a potential liability factor for AD. This polymorphism consists of an insertion or a deletion of a 44-bp fragment in the promoter region of 5-HTT gene; the allele including the 44-bp insertion is called long or ‘‘L’’ allele, while the allele showing the 44-bp deletion is known as short or ‘‘S’’ allele [26, 27]. During the last decades, independent research groups evaluated a possible association between this polymorphism and AD or FTLD, showing conflicting results [28–39]. Hu and colleagues [40] reported significant higher frequency of the short allelic variant in AD patients, compared to controls. More recently, an Italian group identified an impairment of serotonergic transmission in FTLD [38]. Moreover, a synergic effect of COMT Val/Met polymorphism and 5-HTTLPR*S (SS and LS genotypes) variants on the risk of psychosis in AD has been supported [36]. Last year, another Italian research group disconfirmed the role of 5-HTTLPR, as liability factor for AD with or without behavioral alterations [39]. Less than a couple of years ago, the same research team identified a significant correlation between the short 5-HTTLPR allele and sporadic FTLD susceptibility [37]. In the case of FTLD, this deficit could play a role in the hyperorality, disinhibition and perseverative behavior. It is important to notice that the majority of sporadic forms of dementia results from the combination of many genes that could have only subtle effects on biological meaning [41]. In this view, during the year 2002, Conrad and colleagues [42] recognized a new polymorphic gene called saitohin (STH). It is an intronless gene, localized within intron 9 of the microtubule-associated protein tau (MAPT) gene, approximately 2.5-kb downstream of exon 9, on chromosome 17q21, and encodes for a 128 amino acid protein. This region is of great interest because most mutations in FTLD occur in or around this intron and adjacent exons of tau [43]. STH gene shows a similar expression to tau in most human tissues and brain areas, but its biological
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function is not yet clearly known [42]. The authors identified a single nucleotide polymorphism (SNP) [A?G] (rs62063857) that changes a glutamine to arginine at amino acid position 7 (Q7R); the G allele and the GG genotype were found significantly over-represented in LOAD, independently from APOE-4 genotype, suggesting that the STH role in susceptibility to sporadic AD is not dependent from APOE genetic pattern [42]. However, subsequent studies often provided conflicting results, about the possible role of STH polymorphism as liability factor to AD [44–51]. Among positive studies, it is worthwhile to remember papers by Combarros et al. and Seripa et al.: they confirmed Conrad findings [42], reporting that the RR (or GG) genotype is associated with increased risk of LOAD cases in Spanish Caucasians and the R (or G) allele intensified approximately twofold the APOE-4-associated risk of AD in American and Italian Caucasians, respectively [50]. In detail, Seripa and collaborators [50] established that STH G allele could be a ‘‘risk modifier’’ for AD etiology. On the contrary, a number of studies failed to find a statistically significant association between the Q7R polymorphism and AD, in independent sample populations [44–46, 48, 51]. Conflicting findings about STH as liability factor for LOAD could be due to ethnic differences; it is likely that the variation of the STH Q7R polymorphism among different ethnic groups accounts for the varied clinical manifestations of these STH-related diseases [52]. Nevertheless, it is interesting to notice that, besides Verpillat et al. could not confirm the association between the RR (or GG) genotype and LOAD, they found a trend toward an association between the QQ (or AA) genotype and FTLD [45]. Unfortunately, no more convincing studies about possible role of STH in FTLD have been subsequently performed. Anyway, it is interesting to remind that the Q allele has been shown to be also over-represented in other neurodegenerative diseases, including progressive supranuclear palsy [53, 54] and Parkinson disease [55]. Taken together, these results suggest that STH might interact with several proteins, involved in different pathways, becoming a potential actor in these neurodegenerative diseases as well. The aim of our case–control study is to investigate the possible role of 5-HTTLPR and STH polymorphisms (both alone and combined each other) as shared susceptibility factors for AD and FTLD dementia.
Materials and methods Sample Two hundred and eighteen patients, with a diagnosis of sporadic dementia, were consecutively recruited starting
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from 2007 to 2010, at San Raffaele Turro Hospital, Neurological Department of Milan and IRCCS Centro Neurolesi Bonino Pulejo, Neurological Department of Messina. One hundred and sixty-four patients fulfilled criteria for probable AD according to NINCSDS-ADRDA [56], while 54 subjects were diagnosed as FTLD according to Neary criteria [57]. We also collected 54 healthy controls of Italian ethnicity. In detail, the sample consisted of 47 males and 117 females (mean age 75.49 ± 8.28 years; mean age at onset 71.63 ± 8.76 years) with a diagnosis of AD and 30 males and 24 females (mean age 65.40 ± 9.52 years; mean age at onset 62.06 ± 9.28 years) with a diagnosis of FTLD. The healthy subjects, matched for ethnic background, age and gender (28 males and 26 females, mean age 66.79 ± 6.99 years), displayed no cognitive or behavioral complaints and/or psychiatric disorders. Exclusion criteria were history of major depressive disorder, schizophrenia, Parkinson disease or parkinsonism, and drug abuse. All patients were assessed by neurological examination, screening laboratory tests, neuropsychological evaluation and neuroimaging investigation (computed tomography and/or magnetic resonance, FDG-PET or SPET) to establish a clinical diagnosis of dementia according to the standard criteria (DSM IV-r) [58]. The presence of significant vascular brain damage was excluded (Hachinski Ischemic Score \ 4). In order to evaluate cognitive profiles and behavioral disorders, all subjects underwent an extensive neuropsychological battery. Neuropsychiatric Inventory (NPI) [59] and Frontal Behavioural Inventory (FBI) were also administered to the main caregiver. Clinical Dementia Rating (CDR) scale and Instrumental and Basic Activities of daily Living scales (IADL and BADL) were used to assess the global severity and the presence of functional impairment. An informed consent, in accordance with local ethical committee, was obtained from all subjects (or their caregivers). DNA analysis and genotyping assays DNA was extracted from whole blood by manual extraction, using the ‘‘Illustra blood genomicPrep Midi Flow kit’’ (GE Healthcare, Milan, Italy). Serotonin transporter promoter 44-bp ins/del polymorphism (5-HTTLPR) Polymerase chain reaction (PCR) was performed with the following primers: 50 -GGC GTT GCC GCT CTG AAT GC30 and 50 -GAG GGA CTG AGC TGG ACA ACC AC-30 . The PCR reaction was carried out by ABI 9700 PCR thermalcycler (Applied Biosystems, APPLERA) as follows: after a first step at 94°C for 2 min, steps of 94°C for 35 sec, 61°C for 30 sec, 70°C for 65 sec for 35 cycles. Then, a final extension
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step at 70°C for 8 min was added. PCR products were separated in 3.5% Seakem agarose gel with ethidium bromide. The bands were visualized by ultraviolet light. The allele including the 44-bp insertion (also called long or L allele) consists of a fragment of 528 bp, while the allele showing the 44-bp deletion (also known as short or S allele) consists of a fragment of 484 bp. STH A to G substitution (Q7R) PCR was performed with the following primers: 50 -CCC TGT AAA CTC TGA CCA CAC-30 and 50 -ACA GGG AAG CTA CTT CCC ATG-30 . The PCR reaction was carried out by ABI 9700 PCR thermal-cycler (Applied Biosystems, APPLERA) as follows: after a first step at 94°C for 3 min, steps of 94°C for 30 sec, 60°C for 30 sec, 70°C for 30 sec for 35 cycles. Then, a final extension step at 70°C for 6 min was added. PCR product was digested using HinfI (New England Biolabs, England, UK) at 37°C overnight; fragments were separated in 3% Seakem agarose gel with ethidium bromide. The cleaved bands were visualized by ultraviolet light. Depending on the presence of one or two restriction HinfI sites, two fragments 171 ? 55 bp (allele A or allele Q) or three fragments 97 ? 74 ? 55 bp (allele G or allele R) were produced. Statistical analysis Statistical analysis was performed using StatSoft 6.0. The Chi-square (v2) test was used to assess differences of genotype or allele distribution between groups. The significance level was established at p B 0.05, two-tailed. The correction for multiple comparisons (Bonferroni’s correction) was applied. Goodness of fit to Hardy–Weinberg equilibrium (HWE) was tested using the v2 test. The Odds ratio (OR) and the related confidence interval (CI) was determined using MedCalc software (version 8.2.1.0; available at http://www.medcalc.be). The power of the sample was calculated using the O’Brien–Shieh algorithm, as implemented in G*Power 3.0 [60].
Results No deviation from the HWE was observed in all groups, both for serotonin transporter and for the STH polymorphisms (p C 0.05), also when we split demented patients into AD and FTLD. Our study evidenced a possible association between 5-HTTLPR allelic variants and dementia status: patients affected by dementia showed a significant excess of short alleles, compared to healthy subjects (Pearson Chi-
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Neurol Sci (2010) 31:741–749 Table 1 Alleles frequencies for 5-HTTLPR polymorphism in demented versus healthy subjects Diagnosis
5-HTTLPR allelic distribution
Total
L
S
Dementia
234 (53.67%)
202 (46.33%)
Controls
71 (65.74%)
37 (34.26%)
108
Total
305
239
544
436
v2 = 5.12, p value = 0.024, p value threshold after Bonferroni’s correction = 0.025
Table 2 Alleles frequencies for 5-HTTLPR polymorphism in AD versus healthy subjects Diagnosis
5-HTTLPR allelic distribution
Total
L
S
AD
174 (53.05%)
154 (46.95%)
Controls
71 (65.74%)
37 (34.26%)
108
Total
245
191
436
328
v2 = 5.32, p value = 0.021, p value threshold after Bonferroni’s correction = 0.025 Table 3 Genetic frequencies for 5-HTTLPR polymorphism in demented versus healthy subjects (5-HTTLPR*S = SS and LS genotypes) Diagnosis
5-HTTLPR variant distribution
Total
5-HTTLPR*S
LL
Dementia
150 (68.81%)
68 (31.19%)
218
Controls
28 (51.85%)
26 (48.15%)
54
178 (65.44%)
94 (34.56%)
272
Total 2
v = 5.50, p value = 0.019, p value threshold after Bonferroni’s correction = 0.025
square = 5.12, p value = 0.024; Table 1). For this analysis, we had a high power (0.99) to detect a small-medium effect size (w = 0.25) at a type 1 error level of p \ 0.05. The significance of the p value increases up to 0.021, when analyzing the 5-HTTLPR allelic distribution, between the sole AD group versus control one (Pearson Chi-square = 5.32; Table 2). For this analysis, we had a high power (0.99) to detect a small-medium effect size (w = 0.27) at a type 1 error level of p \ 0.05. The p value decreases to 0.019 (Pearson Chisquare = 5.50), grouping subjects according to their genotypes: 5-HTTLPR*S carrier (5-HTTLPR LS and 5-HTTLPR SS genotypes) versus 5-HTTLPR LL genotype. Patients affected by dementia showed a significant excess of the 5-HTTLPR*S carrier, with respect to healthy subjects (Table 3).
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Table 4 Genetic frequencies for 5-HTTLPR polymorphism (5-HTTLPR*S = SS and LS genotypes; AD Alzheimer’s disease) Diagnosis
AD Controls Total
5-HTTLPR variants distribution
Total
Table 6 Interaction between 5-HTTLPR and Q7R STH polymorphisms (5-HTTLPR*S = SS and LS genotypes, STH *G = GG and AG genotypes) in AD (Alzheimer’s disease) versus healthy subjects Diagnosis 5-HTTLPR–STH interaction
5-HTTLPR*S
LL
115 (70.12%)
49 (29.88%)
164
28 (51.85%)
26 (48.15%)
54
143 (70.12%)
75 (29.88%)
218
2
v = 6.00, p value = 0.014, p value threshold after Bonferroni’s correction = 0.025
Total
5-HTTLPR *S
5-HTTLPR LL
STH AA
STH *G
STH AA
AD
77 (47%)
38 (23.2%) 28 (17%)
Controls
12 (22.2%) 16 (29.6%) 16 (29.6%) 10 (18.6%)
Total
89 (40.8%) 54 (24.8%) 44 (20.2%) 31 (14.2%) 218
STH *G 21 (12.8%) 164 54
2
For this analysis, we had a high power (0.99) to detect a medium-large effect size (w = 0.34) at a type 1 error level of p \ 0.05. The same analysis, performed comparing AD subjects and healthy controls, reaches a p value of 0.014 (Pearson Chi-square = 6.00; Table 4); for the present comparison, we had a high power (0.99) to detect a medium-large effect size (w = 0.36) at a type 1 error level of p \ 0.05. As indicated in Tables 1, 2, 3 and 4, all the aforesaid findings survived to the correction for multiple comparisons (Bonferroni’s correction). In contrast to 5-HTTLPR results, the presence of the sole polymorphic Q7R STH variant seems to be not a sufficient susceptibility factor for sporadic dementia outcome in our sample. In detail, we could not detect any significant difference for genotypic and allelic STH gene distribution, also in case of independent analyses between AD and FTLD dementia, versus control group (p value C 0.05). Starting from our positive findings about the 5-HTTLPR polymorphism, we investigated the distribution of Q7R STH variants (grouped into two classes: STH*G carrier and STH AA) in the group of 5-HTTLPR*S carriers. A significant interaction between the 5-HTTLPR and Q7R STH polymorphisms was found comparing demented and healthy subjects (Pearson Chi-square = 10.89, p value = 0.0118; Table 5). In detail, it is interesting to notice that the combination between the 5-HTTLPR*S and the STH AA Table 5 Interaction between 5-HTTLPR and Q7R STH polymorphisms (5-HTTLPR*S = SS and LS genotypes, STH *G = GG and AG genotypes) in demented versus healthy subjects Diagnosis 5-HTTLPR–STH interaction
Total
5-HTTLPR *S
5-HTTLPR LL
STH AA
STH AA
STH *G
STH *G
Dementia 100 (45.9%) 50 (22.9%) 36 (16.5%) 32 (14.7%) 218 Controls Total
12 (22.2%) 16 (29.6%) 16 (29.6%) 10 (18.6%)
54
112 (41.2%) 66 (24.3%) 52 (19.1%) 42 (15.4%) 272
v2 = 10.89; p value = 0.0118, p value threshold after Bonferroni’s correction = 0.0125
v = 10.87; p value = 0.028; p value threshold after Bonferroni’s correction = 0.0125
variants is the more frequent in the demented subjects, while the 5-HTTLPR LL and STH AA combination is the less frequent one (Table 5). For this analysis, we had a high power (1.00) to detect a large effect size (w = 0.59) at a type 1 error level of p \ 0.05. This 5-HTTLPR/STH combination maintained a significant, even if lower, p value also when comparing the group of AD to healthy one (Pearson Chi-square = 10.87, p value = 0.028). Nevertheless, the significance level did not survive to Bonferroni’s correction (p C 0.0125; Table 6). For this latter analysis, we had a high power (1.00) to detect a medium-large effect size (w = 0.61) at a type 1 error level of p \ 0.05. We also performed all the previous analyses for FTLD patients (vs. healthy group), but we did not get significant evidences (p value C 0.05). Finally, to estimate the goodness of the performed association analyses, we calculated the OR, for the most significant results. As summarized in Table 7, the presence of the 5-HTTLPR ‘‘S’’ allele, or SS/LS genotypes (5-HTTLPR S* carrier), or 5-HTTLPR*S/STH AA combination, conferred a significant higher risk (OR [ 1) to develop sporadic dementia, in comparison to healthy subjects. The OR became even more significant, when comparing AD subjects versus healthy ones (Table 7).
Discussion Our study supports the hypothesis that 5-HTTLPR polymorphism could be a susceptibility factor for sporadic dementia, particularly for LOAD. In detail, we observed an excess of short alleles or genotype carrying almost one ‘‘S’’ allele (SS or LS genotypes, the so-called 5-HTTLPR*S carrier) in affected subjects. The 5-HTTLPR short allele is known to determine a significant decrease in serotonin (5-HT) transporter gene transcriptional rate [27] and, therefore, is responsible for a low 5-HT reuptake from the synaptic cleft, even in normal
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Table 7 Odds ratio (OR) calculation for Chi-square analyses providing significance evidence (5-HTTLPR*S carrier = SS and LS genotypes) Chi-square analysis
OR
95% CI
z statistic
p value
5-HTTLPR alleles (Dem vs healthy)
1.66
1.07–2.57
2.25
0.024
5-HTTLPR alleles (AD vs. healthy)
1.70
1.08–2.67
2.29
0.022
5-HTTLPR S* carrier/LL (Dem vs. healthy)
2.05
1.12–3.75
2.32
0.020
5-HTTLPR S* carrier/LL (AD vs. healthy)
2.18
1.16–4.09
2.42
0.015
5-HTTLPR*S carrier/STH AA (Dem vs. healthy)
2.97
1.48–5.94
3.07
0.002
5-HTTLPR*S carrier/STH AA (AD vs. healthy)
3.09
1.52–6.31
3.12
0.002
Dem demented subjects, AD Alzheimer’s disease
human brain. The short allele results also in decreased 5-HTT expression and 5-HT uptake in lymphoblasts, compared with the long allele [61]. Our findings confirmed previous association studies, showing that the low-activity allele of the 5-HTTLPR as a risk factor for LOAD [24, 29, 31, 40] and are in agreement with other recent Italian studies, focused on sporadic dementias [36–39]. These results, besides preliminary, support the hypothetic role of 5-HT in the pathophysiology of neurodegenerative disease [22, 23, 25] and provide a rationale for a pharmacological intervention with selective serotonin reuptake inhibitors (SSRI) in demented patients [62]. Our study also evidenced an interesting and new in literature correlation between 5-HTTLPR and Q7R polymorphisms, suggesting a synergic effect in dementia outcome. In detail, the combination between 5-HTTLPR*S variant and STH AA genotype was significantly more frequent in demented patients than in controls. The significance value of 5-HTTLPR and Q7R polymorphisms interaction was significant (before Bonferroni’s correction), when comparing the single group of AD subjects and healthy ones too. In agreement with another studies [44, 46, 50], our findings did not confirm a direct association between the single STH Q7R variant and dementias, known in literature [42, 45, 49, 54], but indicated the STH Q7R AA genotype, as a relevant ‘‘risk modifier’’ for dementia, in 5-HTTLPR*S carrier. The peculiar localization of STH in a functionally critical position of the tau gene could explain its role in tauopathies [42, 44–51, 53, 54]. As STH nests in the intron between exons 9 and 10 of tau, we cannot exclude the possibility that STH polymorphism, through the regulation of exon 10 alternative splicing, may explain the different expression of tau isoforms in different tauopathies [21]. It is important to remember that exon 10 encodes the second of four possible microtubule binding domains; alternative splicing of exon 10 results in a 4R (with four microtubule binding domain repeats) or 3R (three repeats) form of tau isoforms [63–65]. The 4R-to-3R ratio appears to be essential for preventing neurodegeneration and is probably
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very finely balanced, since a very large portion of the general population develops limited filamentous tau pathology with aging [66]. Therefore, functional studies of STH could be very important in disclosing whether it plays a role in tau splicing or in the related tau phosphorylation [54]. Moreover, we have to remember that STH gene is in linkage disequilibrium with two conserved haplotypes within the MAPT gene, the so-called H1 and H2, including eight SNPs [53, 67–69] and one with a microsatellite marker [70]. Besides a considerable literature on the genetic associations of the MAPT haplotypes with tauopathies was available [70–77], there is no clear evidence as to how these haplotypes may influence the clinical course or neuropathological processes of tauopathies. In this view, the STH Q7R polymorphisms, being in linkage disequilibrium with H1/H2 haplotypes, could play a not already revealed role. To conclude, we might hypothesize that the STH Q7R polymorphism, in synergy with the 5-HTTLPR variant, could predispose to the pathogenesis of sporadic dementias. The conflicting results, about sporadic dementia, known in literature up to date, could be partially explained, evaluating not only the influence of a single polymorphic gene on dementia etiology, but, overall the interaction among different genes, if taken alone, could also have only subtle biological effects. For the future, we aim to enlarge our sample, in order to confirm present findings. The next step could be understanding the molecular bases of serotonin transporter and STH genes interaction. Our study, although preliminary, provides some pertinent contributions to the knowledge of the genetic bases of neurodegenerative diseases.
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