Neuroscience Letters 557 (2013) 177–180
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Association of a polymorphism in mitochondrial transcription factor A (TFAM) with Parkinson’s disease dementia but not dementia with Lewy bodies Ariana P. Gatt, Emma L. Jones, Paul T. Francis, Clive Ballard, Joseph M. Bateman ∗ Wolfson Centre for Age-Related Diseases, King’s College London, Guy’s Campus, London SE1 1UL, UK
h i g h l i g h t s • • • •
TFAM SNP rs2306604 genotype frequency was significantly different to controls in PDD but not DLB. TFAM SNP rs2306604 A allele was associated with PDD but not DLB. rs2306604 A allele was strongly associated with PDD in males but not in females. Genetic factors predisposing to dementia may differ in PDD and DLB.
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Article history: Received 3 June 2013 Received in revised form 16 October 2013 Accepted 18 October 2013 Keywords: Lewy body Dementia Parkinson’s TFAM Mitochondria Polymorphism
a b s t r a c t The single nucleotide polymorphism (SNP) A > G rs2306604 in the gene encoding mitochondrial transcription factor A (TFAM) has been associated with Alzheimer’s disease, with the A allele being recognised as a risk factor, but has not been studied in other types of dementia. We hypothesised that TFAM SNP rs2306604 might also be associated with Lewy body dementias. To test this hypothesis rs2306604 genotype was determined in 141 controls and 135 patients with dementia with Lewy bodies (DLB) or Parkinson’s disease dementia (PDD). rs2306604 genotype frequencies were significantly different to controls in PDD (p = 0.042), but not in DLB (p = 0.529). The A allele was also associated with PDD (p = 0.024, OR = 2.092), but not DLB (p = 0.429, OR = 1.308). Moreover, the A allele was strongly associated with PDD in males (p = 0.001, OR = 5.570), but not in females (p = 0.832, OR = 1.100). Mitochondrial DNA copy number in the prefrontal cortex was also significantly reduced in PDD patients, but this reduction was not associated with rs2306604 genotype. These data show that the TFAM SNP rs2306604 A allele may be a risk factor for PDD, particularly in males, but not for DLB. Therefore, the genetic factors that predispose individuals to develop dementia may differ in PDD and DLB. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lewy body (LB) dementias are characterised pathologically by the presence of intraneuronal Lewy bodies containing ␣-synuclein and ubiquitin [22]. LB dementia can occur either concurrently with motor symptoms or in patients with idiopathic Parkinson’s disease (PD) and are referred to as dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) respectively. DLB and PDD have several common clinical and pathological features, but are separated diagnostically by the timing of onset of dementia in relation to motor symptoms [18]. PDD develops within 25–30% of PD patients with prevalence tending to increase with age, such that the cumulative prevalence may be as high as 75% of patients with PD
∗ Corresponding author. Tel.: +44 207 848 8144; fax: +44 207 848 6816. E-mail address: joseph [email protected] (J.M. Bateman). 0304-3940/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2013.10.045
for longer than 10 years [2,4]. The two dementia types present similar pathologies with spherical Lewy bodies and filamentous Lewy neurites, which are both primarily composed of alpha-synuclein, being widespread throughout the brain stem, neocortex and the limbic and forebrain regions in both cases [18]. Neuropsychological profiles of the two dementias are also similar with both DLB and PDD presenting attention deficits, impairments in language and executive function, visuospatial function, memory and behaviour [21]. However, differences in the clinical features between DLB and PDD have been described, such as more conceptual and attentional errors and more hallucinations and psychoses in DLB than PDD patients [1,3,11,24]. DLB patients also have fewer signs of parkinsonism, at least initially, although this will eventually develop in the majority of DLB patients [8]. Mitochondrial transcription factor A (TFAM) is a nuclear encoded protein that is essential for the transcription, replication and packaging of mitochondrial DNA (mtDNA). The TFAM single
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Table 1 Genotype distribution and allele frequencies [n (%)] of rs2306604 TFAM A/G polymorphism in controls, DLB and PDD samples. Control n = 141 AA (%) AG (%) GG (%) 2 , d.f. p-Value AA AG/GG p-Value Odds ratio CI
39 (27.7) 70 (49.6) 32 (22.7)
39 (27.7) 102 (72.3)
DLB/PDD n = 135
DLB n = 72
PDD n = 63
52 (38.5) 51 (37.8) 32 (23.7) 4.712, 2 0.095 52 (38.5) 83 (61.5) 0.073 1.639 0.9875–2.719
24 (33.3) 30 (41.7) 18 (25.0) 1.273, 2 0.529 24 (33.3) 48 (66.7) 0.429 1.308 0.7080–2.415
28 (44.4) 21 (33.3) 14 (22.2) 6.337, 2 0.042 28 (44.4) 35 (55.6) 0.024 2.092 1.127–3.886
d.f.: degrees of freedom. CI: confidence interval.
nucleotide polymorphism (SNP) rs2306604 (IVS4 + 113A > G), located in intron 4, has been associated with Alzheimer’s disease (AD) in a 2007 meta-analysis of several small-scale studies and in a recent French genome wide association study [7,17]. In both these studies the A allele was associated with AD. Studies of PD patients are equivocal, showing no association with rs2306604 [6], or an increased risk of PD to be associated with the G allele [13]. rs2306604 has a global minor allele frequency of A = 0.461 and an average European minor allele frequency of A = 0.400 [25]. DLB cases frequently exhibit AD-like pathology, including cortical amyloid plaques along with PD-like parkinsonian features and ␣-synuclein aggregates [5]. However, there have been no studies investigating the association of TFAM gene variants with DLB or PDD. We hypothesised that TFAM SNP rs2306604 might be associated with DLB and PDD, or that its association might distinguish between the two dementias.
centres. Brain tissue was made available under delegated Ethics approval to each brain bank.
2. Methods
2.4. Statistical analysis
2.1. Population
Statistical analyses were performed using SPSS Version 19 and GraphPad Prism Version 5.0. Pearson’s 2 test was used to compare genotype frequency between dementia cases and controls while Fischer’s exact test was used to compare 2 × 2 contingency of allele frequencies between cases and controls. Differences in demographic and clinical features were tested using a Student’s t-test. The Mann–Whitney test was used to compare mtDNA levels.
Tissue and data were collected from a number of UK and Scandinavian clinical cohorts and tissue resources (postoperative cognitive decline trial, King’s College London, UK; Newcastle Brain Tissue Resource, London Neurodegenerative Diseases Brain Bank and Thomas Willis Oxford Brain Collection, as part of the Brains for Dementia Research initiative, UK; Demvest clinical and pathological study in Stavanger, Norway; a dementia patient cohort in Malmö, Sweden). All patients were prospectively followed. A total of 276 DNA samples were prepared from brain or blood of individuals for TFAM rs2306604 SNP genotyping. 72 DNA samples were obtained from DLB patients (50.0% males, mean ± SD age = 76.21 ± 6.85 years), 63 from PDD patients (49.2% males, mean ± SD age = 77.02 ± 6.69 years,) and 141 samples from controls (39.7% males, mean ± SD age = 76.34 ± 7.93 years). There was no significant difference between the mean age of controls and DLB or PDD patients. Of the total, 106 were from brain samples with pathologically confirmed diagnoses: 22 DLB, 36 PDD and 48 controls, the rest of the cases were blood samples. Diagnoses of DLB were made according to the McKeith consensus criteria [21]. PDD was diagnosed based upon the presence of PD according to the UK brain bank criteria [16], a diagnosis of dementia according to DSM-IV criteria and the occurrence of PD for more than one year before the onset of dementia [21]. Controls had no evidence of dementia based upon clinical history and those from whom brain samples were available did not have sufficient pathology to meet diagnostic criteria for any form of dementia at postmortem examination. The clinical and autopsy aspects of the study were fully approved by Human Subjects Research Ethics Committees in each of the
2.2. Genotyping Genomic DNA was extracted using a commercially available kit (DNeasy blood and tissue kit, Qiagen). The TFAM rs2306604 SNP was genotyped in duplicate using a Taqman SNP genotyping assay (Applied Biosystems, C 1953826 1) and an ABI 7000 Sequence Detection System (Applied Biosystems). 2.3. Quantitative PCR (qPCR) of mtDNA levels qPCR of mtDNA levels was performed as in [19] using the SensiMix SYBR no-ROX Kit (Bioline) in a Rotor Gene 6000 Cycler (Qiagen).
3. Results Table 1 shows the comparison of TFAM SNP rs2306604 genotype and allele frequencies in DLB and PDD patients to control subjects. rs2306604 genotype frequencies were not significantly different from controls in the combined DLB/PDD patient cohort (2 = 4.712, p = 0.095) (Table 1). However, genotype frequencies were significantly different between controls and PDD patients (2 = 6.337, p = 0.042). Analysing the frequency of the rs2306604 AA genotype compared to the rest of the genotypes pooled together (AG and GG), also revealed a significant difference in the PDD patients (p = 0.024, OR = 2.092) (Table 1). There was no significant difference in rs2306604 genotype distribution between controls and DLB patients (2 = 1.273, p = 0.529). Frequency of the AA allele compared to AG/GG (p = 0.429, OR = 1.308) was also unchanged in DLB patients compared to controls (Table 1). Stratification of the samples according to gender revealed that SNP rs2306604 genotype frequencies in the PDD male group were significantly different to the male controls (2 = 12.37, p = 0.002) (Table 2). Homozygosity for the A allele was also found to be strongly associated with an increased risk of PDD in males (p = 0.001, OR = 5.570) compared with AG/GG carriers (Table 2). Analysing rs2306604 genotype distribution in the female PDD
A.P. Gatt et al. / Neuroscience Letters 557 (2013) 177–180
179
Fig. 1. mtDNA levels are reduced in PDD. (A) mtDNA/nDNA ratio is significantly decreased in PDD patient prefrontal cortex. Controls n = 13; PDD n = 23. (B) There is no significant difference in mtDNA/nDNA ratio between rs2306604 genotypes in PDD patient prefrontal cortex. AA n = 8; AG n = 8; GG n = 6. Data are represented as mean ± S.E.M. ***p ≤ 0.001.
Table 2 Genotype distribution and allele frequencies [n (%)] of rs2306604 TFAM A/G polymorphism in control, DLB and PDD males.
AA (%) AG (%) GG (%) 2 , d.f. p-Value AA (%) AG/GG (%) p-Value Odds ratio CI
Control n = 56
DLB n = 36
PDD n = 31
9 (16.1) 30 (53.6) 17 (30.4)
11 (30.6) 17 (47.2) 8 (22.2) 2.821, 2 0.244 11 (30.6) 25 (69.4) 0.124 2.298 0.8403–6.283
16 (51.6) 9 (29.0) 6 (19.4) 12.37, 2 0.002 16 (51.6) 15 (48.4) 0.001 5.570 2.044–15.18
9 (16.1) 47 (83.9)
d.f.: degrees of freedom. CI: confidence interval.
patients revealed no significant associations with the rs2306604 AA genotype or A allele (Supplementary Table 1), suggesting that the presence of TFAM rs2306604 A allele might be a risk factor for PDD in males but not in females. No change in rs2306604 genotype frequency was found in the DLB male population (2 = 2.821, p = 0.244), nor was there an association of the rs2306604 A allele (p = 0.124, OR = 2.298) with DLB in males (Table 2). To determine if mtDNA levels were affected in PDD patients qPCR of mtDNA isolated from Brodmann area 9 (prefrontal cortex) from 13 controls and 23 PDD patients was performed. mtDNA levels were significantly decreased in PDD patients (Fig. 1A). However, there was no significant change in mtDNA levels associated with rs2306604 genotype (Fig. 1B), nor with rs2306604 genotype stratified according to gender (Supplementary Fig. 1). 4. Discussion The results presented here suggest that TFAM SNP rs2306604 may be a risk factor for PDD, but not DLB. There have been difficulties in defining a diagnostic boundary between DLB and PDD and the third report of the DLB Consortium highlighted this issue [21]. The conclusion was that DLB and PDD should be grouped together in one term for molecular and genetic studies leading to therapeutic development. Our study however, suggests that there may be different genetic risk factors for each disease. In the case of TFAM there may be a particularly strong association with PDD, but not DLB, in males. Studies with larger patient groups will be required to confirm the results presented here and to identify other polymorphisms that potentially distinguish DLB and PDD. Men are reported to be at 1.5 times greater risk of developing PD than women [28], although the biological basis for this bias is not known. The increased risk to males carrying the TFAM SNP rs2306604 A allele of developing PDD may, if replicated in other studies, suggest either an interaction of TFAM with a sexually
dimorphic factor such as Sry, which is expressed in the frontal cortex in the male brain [20], or some primary environmental risk factor to which men have greater exposure. Studies investigating the involvement of TFAM SNP rs2306604 in AD have found no gender bias in the association [7,17]. However, TFAM SNP G > C rs1937 has been found to be predominantly associated with AD in females [15]. APOE 4, a known genetic risk factor for AD, was also found to be more predominant in females [15]. Therefore, gender bias may be a common feature of the association of specific SNPs with neurodegenerative disease. Mitochondrial dysfunction has been widely implicated in neurodegenerative diseases including AD and PD. As a regulator of mtDNA transcription and replication and a controller of mtDNA copy number, TFAM has been well studied for its potential role in neurodegeneration. In vivo mouse models have been used to study the involvement of TFAM in PD development [12,14]. Furthermore, several studies have suggested a potential role for TFAM in mitochondrial therapy for neurodegenerative disorders. TFAM overexpression has been shown to attenuate -amyloid-induced oxidative damage in SH-SY5Y cells [29], as well as delay the onset of disease in a mouse model of amyotrophic lateral sclerosis [23]. Treatment with recombinant human TFAM (rhTFAM) has been shown to reduce oxidative stress and increase ATP levels and viability in vitro and also to increase mtDNA copy number and complex I protein levels in vivo [26]. Injections of rhTFAM have also been shown to improve memory and mitochondrial respiration in ageing mice [27]. These studies all suggest an involvement of TFAM in maintaining a healthy respiratory chain and mitochondrial function, and indicate that alterations in TFAM might be implicated in neurodegeneration. The data presented here suggest that the TFAM rs2306604 A allele is associated with an increased risk of developing PDD. Whether TFAM SNP rs2306604 affects protein function is not known. rs2306604 is located in intron 4 and it has been suggested that this SNP may affect TFAM splicing [6]. Analysis of mtDNA levels from prefrontal cortex showed that PDD patients had a significantly lower mtDNA copy number than controls (Fig. 1A). Reduced mtDNA copy number is seen in a group of mitochondrial disorders known as ‘mtDNA depletion syndrome’ and has also been described in AD [9,10]. However, no association was found between mtDNA copy number and rs2306604 genotype (Fig. 1B). These data suggest that rs2306604 genotype does not affect mtDNA copy number. However, larger studies will be required to confirm these data. Moreover, changes in mtDNA copy number could differ between individual neurons and so use of laser microdissection to isolate DNA from single neurons may identify changes that cannot be observed in tissue homogenate. Future studies will also determine whether TFAM expression is differentially affected at the mRNA or protein level in DLB or PDD patients and whether any changes correlate with rs2306604 genotype.
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Association of a polymorphism in mitochondrial transcription factor A (TFAM) with Parkinson’s disease dementia but not dementia with Lewy bodies Ariana P. Gatt, Emma L. Jones, Paul T. Francis, Clive Ballard, Joseph M. Bateman ∗ Wolfson Centre for Age-Related Diseases, King’s College London, Guy’s Campus, London SE1 1UL, UK
h i g h l i g h t s • • • •
TFAM SNP rs2306604 genotype frequency was significantly different to controls in PDD but not DLB. TFAM SNP rs2306604 A allele was associated with PDD but not DLB. rs2306604 A allele was strongly associated with PDD in males but not in females. Genetic factors predisposing to dementia may differ in PDD and DLB.
a r t i c l e
i n f o
Article history: Received 3 June 2013 Received in revised form 16 October 2013 Accepted 18 October 2013 Keywords: Lewy body Dementia Parkinson’s TFAM Mitochondria Polymorphism
a b s t r a c t The single nucleotide polymorphism (SNP) A > G rs2306604 in the gene encoding mitochondrial transcription factor A (TFAM) has been associated with Alzheimer’s disease, with the A allele being recognised as a risk factor, but has not been studied in other types of dementia. We hypothesised that TFAM SNP rs2306604 might also be associated with Lewy body dementias. To test this hypothesis rs2306604 genotype was determined in 141 controls and 135 patients with dementia with Lewy bodies (DLB) or Parkinson’s disease dementia (PDD). rs2306604 genotype frequencies were significantly different to controls in PDD (p = 0.042), but not in DLB (p = 0.529). The A allele was also associated with PDD (p = 0.024, OR = 2.092), but not DLB (p = 0.429, OR = 1.308). Moreover, the A allele was strongly associated with PDD in males (p = 0.001, OR = 5.570), but not in females (p = 0.832, OR = 1.100). Mitochondrial DNA copy number in the prefrontal cortex was also significantly reduced in PDD patients, but this reduction was not associated with rs2306604 genotype. These data show that the TFAM SNP rs2306604 A allele may be a risk factor for PDD, particularly in males, but not for DLB. Therefore, the genetic factors that predispose individuals to develop dementia may differ in PDD and DLB. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lewy body (LB) dementias are characterised pathologically by the presence of intraneuronal Lewy bodies containing ␣-synuclein and ubiquitin [22]. LB dementia can occur either concurrently with motor symptoms or in patients with idiopathic Parkinson’s disease (PD) and are referred to as dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) respectively. DLB and PDD have several common clinical and pathological features, but are separated diagnostically by the timing of onset of dementia in relation to motor symptoms [18]. PDD develops within 25–30% of PD patients with prevalence tending to increase with age, such that the cumulative prevalence may be as high as 75% of patients with PD
∗ Corresponding author. Tel.: +44 207 848 8144; fax: +44 207 848 6816. E-mail address: joseph [email protected] (J.M. Bateman). 0304-3940/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2013.10.045
for longer than 10 years [2,4]. The two dementia types present similar pathologies with spherical Lewy bodies and filamentous Lewy neurites, which are both primarily composed of alpha-synuclein, being widespread throughout the brain stem, neocortex and the limbic and forebrain regions in both cases [18]. Neuropsychological profiles of the two dementias are also similar with both DLB and PDD presenting attention deficits, impairments in language and executive function, visuospatial function, memory and behaviour [21]. However, differences in the clinical features between DLB and PDD have been described, such as more conceptual and attentional errors and more hallucinations and psychoses in DLB than PDD patients [1,3,11,24]. DLB patients also have fewer signs of parkinsonism, at least initially, although this will eventually develop in the majority of DLB patients [8]. Mitochondrial transcription factor A (TFAM) is a nuclear encoded protein that is essential for the transcription, replication and packaging of mitochondrial DNA (mtDNA). The TFAM single
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Table 1 Genotype distribution and allele frequencies [n (%)] of rs2306604 TFAM A/G polymorphism in controls, DLB and PDD samples. Control n = 141 AA (%) AG (%) GG (%) 2 , d.f. p-Value AA AG/GG p-Value Odds ratio CI
39 (27.7) 70 (49.6) 32 (22.7)
39 (27.7) 102 (72.3)
DLB/PDD n = 135
DLB n = 72
PDD n = 63
52 (38.5) 51 (37.8) 32 (23.7) 4.712, 2 0.095 52 (38.5) 83 (61.5) 0.073 1.639 0.9875–2.719
24 (33.3) 30 (41.7) 18 (25.0) 1.273, 2 0.529 24 (33.3) 48 (66.7) 0.429 1.308 0.7080–2.415
28 (44.4) 21 (33.3) 14 (22.2) 6.337, 2 0.042 28 (44.4) 35 (55.6) 0.024 2.092 1.127–3.886
d.f.: degrees of freedom. CI: confidence interval.
nucleotide polymorphism (SNP) rs2306604 (IVS4 + 113A > G), located in intron 4, has been associated with Alzheimer’s disease (AD) in a 2007 meta-analysis of several small-scale studies and in a recent French genome wide association study [7,17]. In both these studies the A allele was associated with AD. Studies of PD patients are equivocal, showing no association with rs2306604 [6], or an increased risk of PD to be associated with the G allele [13]. rs2306604 has a global minor allele frequency of A = 0.461 and an average European minor allele frequency of A = 0.400 [25]. DLB cases frequently exhibit AD-like pathology, including cortical amyloid plaques along with PD-like parkinsonian features and ␣-synuclein aggregates [5]. However, there have been no studies investigating the association of TFAM gene variants with DLB or PDD. We hypothesised that TFAM SNP rs2306604 might be associated with DLB and PDD, or that its association might distinguish between the two dementias.
centres. Brain tissue was made available under delegated Ethics approval to each brain bank.
2. Methods
2.4. Statistical analysis
2.1. Population
Statistical analyses were performed using SPSS Version 19 and GraphPad Prism Version 5.0. Pearson’s 2 test was used to compare genotype frequency between dementia cases and controls while Fischer’s exact test was used to compare 2 × 2 contingency of allele frequencies between cases and controls. Differences in demographic and clinical features were tested using a Student’s t-test. The Mann–Whitney test was used to compare mtDNA levels.
Tissue and data were collected from a number of UK and Scandinavian clinical cohorts and tissue resources (postoperative cognitive decline trial, King’s College London, UK; Newcastle Brain Tissue Resource, London Neurodegenerative Diseases Brain Bank and Thomas Willis Oxford Brain Collection, as part of the Brains for Dementia Research initiative, UK; Demvest clinical and pathological study in Stavanger, Norway; a dementia patient cohort in Malmö, Sweden). All patients were prospectively followed. A total of 276 DNA samples were prepared from brain or blood of individuals for TFAM rs2306604 SNP genotyping. 72 DNA samples were obtained from DLB patients (50.0% males, mean ± SD age = 76.21 ± 6.85 years), 63 from PDD patients (49.2% males, mean ± SD age = 77.02 ± 6.69 years,) and 141 samples from controls (39.7% males, mean ± SD age = 76.34 ± 7.93 years). There was no significant difference between the mean age of controls and DLB or PDD patients. Of the total, 106 were from brain samples with pathologically confirmed diagnoses: 22 DLB, 36 PDD and 48 controls, the rest of the cases were blood samples. Diagnoses of DLB were made according to the McKeith consensus criteria [21]. PDD was diagnosed based upon the presence of PD according to the UK brain bank criteria [16], a diagnosis of dementia according to DSM-IV criteria and the occurrence of PD for more than one year before the onset of dementia [21]. Controls had no evidence of dementia based upon clinical history and those from whom brain samples were available did not have sufficient pathology to meet diagnostic criteria for any form of dementia at postmortem examination. The clinical and autopsy aspects of the study were fully approved by Human Subjects Research Ethics Committees in each of the
2.2. Genotyping Genomic DNA was extracted using a commercially available kit (DNeasy blood and tissue kit, Qiagen). The TFAM rs2306604 SNP was genotyped in duplicate using a Taqman SNP genotyping assay (Applied Biosystems, C 1953826 1) and an ABI 7000 Sequence Detection System (Applied Biosystems). 2.3. Quantitative PCR (qPCR) of mtDNA levels qPCR of mtDNA levels was performed as in [19] using the SensiMix SYBR no-ROX Kit (Bioline) in a Rotor Gene 6000 Cycler (Qiagen).
3. Results Table 1 shows the comparison of TFAM SNP rs2306604 genotype and allele frequencies in DLB and PDD patients to control subjects. rs2306604 genotype frequencies were not significantly different from controls in the combined DLB/PDD patient cohort (2 = 4.712, p = 0.095) (Table 1). However, genotype frequencies were significantly different between controls and PDD patients (2 = 6.337, p = 0.042). Analysing the frequency of the rs2306604 AA genotype compared to the rest of the genotypes pooled together (AG and GG), also revealed a significant difference in the PDD patients (p = 0.024, OR = 2.092) (Table 1). There was no significant difference in rs2306604 genotype distribution between controls and DLB patients (2 = 1.273, p = 0.529). Frequency of the AA allele compared to AG/GG (p = 0.429, OR = 1.308) was also unchanged in DLB patients compared to controls (Table 1). Stratification of the samples according to gender revealed that SNP rs2306604 genotype frequencies in the PDD male group were significantly different to the male controls (2 = 12.37, p = 0.002) (Table 2). Homozygosity for the A allele was also found to be strongly associated with an increased risk of PDD in males (p = 0.001, OR = 5.570) compared with AG/GG carriers (Table 2). Analysing rs2306604 genotype distribution in the female PDD
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Fig. 1. mtDNA levels are reduced in PDD. (A) mtDNA/nDNA ratio is significantly decreased in PDD patient prefrontal cortex. Controls n = 13; PDD n = 23. (B) There is no significant difference in mtDNA/nDNA ratio between rs2306604 genotypes in PDD patient prefrontal cortex. AA n = 8; AG n = 8; GG n = 6. Data are represented as mean ± S.E.M. ***p ≤ 0.001.
Table 2 Genotype distribution and allele frequencies [n (%)] of rs2306604 TFAM A/G polymorphism in control, DLB and PDD males.
AA (%) AG (%) GG (%) 2 , d.f. p-Value AA (%) AG/GG (%) p-Value Odds ratio CI
Control n = 56
DLB n = 36
PDD n = 31
9 (16.1) 30 (53.6) 17 (30.4)
11 (30.6) 17 (47.2) 8 (22.2) 2.821, 2 0.244 11 (30.6) 25 (69.4) 0.124 2.298 0.8403–6.283
16 (51.6) 9 (29.0) 6 (19.4) 12.37, 2 0.002 16 (51.6) 15 (48.4) 0.001 5.570 2.044–15.18
9 (16.1) 47 (83.9)
d.f.: degrees of freedom. CI: confidence interval.
patients revealed no significant associations with the rs2306604 AA genotype or A allele (Supplementary Table 1), suggesting that the presence of TFAM rs2306604 A allele might be a risk factor for PDD in males but not in females. No change in rs2306604 genotype frequency was found in the DLB male population (2 = 2.821, p = 0.244), nor was there an association of the rs2306604 A allele (p = 0.124, OR = 2.298) with DLB in males (Table 2). To determine if mtDNA levels were affected in PDD patients qPCR of mtDNA isolated from Brodmann area 9 (prefrontal cortex) from 13 controls and 23 PDD patients was performed. mtDNA levels were significantly decreased in PDD patients (Fig. 1A). However, there was no significant change in mtDNA levels associated with rs2306604 genotype (Fig. 1B), nor with rs2306604 genotype stratified according to gender (Supplementary Fig. 1). 4. Discussion The results presented here suggest that TFAM SNP rs2306604 may be a risk factor for PDD, but not DLB. There have been difficulties in defining a diagnostic boundary between DLB and PDD and the third report of the DLB Consortium highlighted this issue [21]. The conclusion was that DLB and PDD should be grouped together in one term for molecular and genetic studies leading to therapeutic development. Our study however, suggests that there may be different genetic risk factors for each disease. In the case of TFAM there may be a particularly strong association with PDD, but not DLB, in males. Studies with larger patient groups will be required to confirm the results presented here and to identify other polymorphisms that potentially distinguish DLB and PDD. Men are reported to be at 1.5 times greater risk of developing PD than women [28], although the biological basis for this bias is not known. The increased risk to males carrying the TFAM SNP rs2306604 A allele of developing PDD may, if replicated in other studies, suggest either an interaction of TFAM with a sexually
dimorphic factor such as Sry, which is expressed in the frontal cortex in the male brain [20], or some primary environmental risk factor to which men have greater exposure. Studies investigating the involvement of TFAM SNP rs2306604 in AD have found no gender bias in the association [7,17]. However, TFAM SNP G > C rs1937 has been found to be predominantly associated with AD in females [15]. APOE 4, a known genetic risk factor for AD, was also found to be more predominant in females [15]. Therefore, gender bias may be a common feature of the association of specific SNPs with neurodegenerative disease. Mitochondrial dysfunction has been widely implicated in neurodegenerative diseases including AD and PD. As a regulator of mtDNA transcription and replication and a controller of mtDNA copy number, TFAM has been well studied for its potential role in neurodegeneration. In vivo mouse models have been used to study the involvement of TFAM in PD development [12,14]. Furthermore, several studies have suggested a potential role for TFAM in mitochondrial therapy for neurodegenerative disorders. TFAM overexpression has been shown to attenuate -amyloid-induced oxidative damage in SH-SY5Y cells [29], as well as delay the onset of disease in a mouse model of amyotrophic lateral sclerosis [23]. Treatment with recombinant human TFAM (rhTFAM) has been shown to reduce oxidative stress and increase ATP levels and viability in vitro and also to increase mtDNA copy number and complex I protein levels in vivo [26]. Injections of rhTFAM have also been shown to improve memory and mitochondrial respiration in ageing mice [27]. These studies all suggest an involvement of TFAM in maintaining a healthy respiratory chain and mitochondrial function, and indicate that alterations in TFAM might be implicated in neurodegeneration. The data presented here suggest that the TFAM rs2306604 A allele is associated with an increased risk of developing PDD. Whether TFAM SNP rs2306604 affects protein function is not known. rs2306604 is located in intron 4 and it has been suggested that this SNP may affect TFAM splicing [6]. Analysis of mtDNA levels from prefrontal cortex showed that PDD patients had a significantly lower mtDNA copy number than controls (Fig. 1A). Reduced mtDNA copy number is seen in a group of mitochondrial disorders known as ‘mtDNA depletion syndrome’ and has also been described in AD [9,10]. However, no association was found between mtDNA copy number and rs2306604 genotype (Fig. 1B). These data suggest that rs2306604 genotype does not affect mtDNA copy number. However, larger studies will be required to confirm these data. Moreover, changes in mtDNA copy number could differ between individual neurons and so use of laser microdissection to isolate DNA from single neurons may identify changes that cannot be observed in tissue homogenate. Future studies will also determine whether TFAM expression is differentially affected at the mRNA or protein level in DLB or PDD patients and whether any changes correlate with rs2306604 genotype.
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