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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 63:467-473 (2008)
© 2008 The Gerontological Society of America

A Percentage Analysis of the Telomere Length in Parkinson's Disease Patients

Jing Zhi Guan, Toyoki Maeda, Masahiro Sugano, Jun-ichi Oyama, Yoshihiro Higuchi, Tomokazu Suzuki and Naoki Makino

1 Division of Molecular and Clinical Gerontology, Department of Molecular and Cellular Biology and 2 Division of Clinical Genetics, Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.

Address correspondence to Toyoki Maeda, MD, PhD, 4546, Tsurumihara, Beppu, Oita, 874-0838, Japan. E-mail: maedat{at}beppu.kyushu-u.ac.jp


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Telomeres are the repeated sequences at the chromosome ends which undergo shortening with cell division. The telomere shortening of the peripheral leukocytes is also facilitated by enhanced oxidative stress in various kinds of disease including ischemic heart disease, diabetes mellitus, apoplexy, and Alzheimer's disease. Telomere shortening in Parkinson's disease (PD) has not yet been reported. The pathogenesis for PD is also regarded to be associated with oxidative stress. We investigated 28 Japanese male PD patients ages 47–69. Although we could not find a statistical difference in the mean telomere length of peripheral leukocytes between the PD patients and the control participants, we found the mean telomere lengths to be shorter than 5 kb in only the PD patients and a significant PD-associated decrease in the telomeres with a length ranging from 23.1 to 9.4 kb in the patients in their 50s and 60s. These observations suggest that telomere shortening is accelerated in PD patients in comparison to the normal population.

Key Words: Telomere • Parkinson's disease • Aging • Oxidative stress • Cell senescence

TELOMERES are the extreme ends of chromosomal DNA, and they are involved in maintaining cellular stability (1,2). They become progressively shorter after repeated cell division because the DNA polymerase cannot fully complete the replication of the 3' end of linear DNA (3), so the telomere shortening has been regarded to represent cellular aging. Moreover, the mean telomere length of peripheral leukocytes becomes shorter with aging (3–5). This telomere shortening of peripheral leukocytes indicates that the telomere can be a tool to evaluate not only cellular aging but also systemic aging.

Recently, the telomere length in peripheral blood cells has been used as the primary model in attempts to decipher links among aging, age-related disorders, and telomere dynamics in humans (6). Acceleration of telomere shortening in peripheral blood cells of people with an age-related disease has been suggested to be related to increased systemic oxidative stress and chronic inflammation in the disease condition (6,7). It was suggested that terminal restriction fragment (TRF) measurement in easily accessible specimens such as peripheral blood could serve as a surrogate parameter for the relative telomere length in other tissues (8), and peripheral blood leukocytes are an excellent source for investigating how telomeres shorten (9). Therefore, telomere shortening in peripheral blood leukocytes can serve not only as a marker of aging but as that of the accumulated oxidative stress and chronic inflammation, which can be an indicator of systemic pathological stress accompanying disease conditions (10). For example, the mean leukocyte TRF length in myocardial infarction patients was significantly shorter than that of the controls and increased the risk of myocardial infarction by approximately 3-fold (11). Similarly, the telomeres of endothelial cells associated with coronary atherosclerosis were markedly shortened, suggesting that they may play a pathogenic role in coronary arterial diseases (12).

Pathophysiological telomere shortening in peripheral blood cells has been also reported in other various pathological conditions (including diabetes mellitus, Alzheimer's disease, smoking, and obesity) and in mothers with a high degree of psychological stress related to child care for ill children (13–16). Under these conditions, it is suggested that telomere erosion-inducing factors including oxidative stress and accelerated cell turnover are associated with pathogenesis of the pathological conditions.

Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by a progressive degeneration of dopamine-containing neurons. The oxidative stress hypothesis (17) and chronic inflammation on the dopaminergic cells of the substantia nigra (18) have been supported by previous studies (19–21). A number of therapies targeting inflammation and mitochondrial dysfunction, which can be caused by abnormally or excessively enhanced oxidative stress, are efficacious in the model of PD (19). From these reports, it can be hypothesized that telomere length shortening may be accelerated in PD patients. Telomere length in peripheral leukocytes can be an indicator of systemic PD-associated damages caused by oxidative stress and increased leukocyte turnover with chronic inflammation, which accelerate age-related telomere length changes. So far, there has been no report of telomere shortening in PD. As a result, we decided to analyze PD-associated telomere length change.

We attempted to analyze the telomere length distribution adding to an analysis of the mean telomere length. Organ-specific telomere length change of rate with aging was determined, not by comparing the mean telomere length change, but by comparing the telomere length distribution among various organs, thus indicating that analysis of telomere length distribution can more sensitively detect telomere length change than can an analysis of the mean telomere length (22). Our previous study showed that size distribution of telomere length in healthy Japanese persons also provided confounding aspects of age- and gender-related telomere change (5). We previously reported that percentages of telomeres longer than 9.4 kb and shorter than 4.4 kb reflected aging-related mean TRF (mTRF) shortening with higher sensitivity than the simple mTRF-based analysis. We herein analyzed PD patients who were mainly in their 50s and 60s. A combined analysis with mTRF and telomere length distribution is expected to be helpful to detect aging- and PD-related telomere length change in such a small age range. We therefore decided to analyze not only mTRF but size distribution of telomere length in peripheral leukocytes in PD patients in comparison to the healthy controls to detect any slight differences in the telomere length between them.


   MATERIALS AND METHODS
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Results
 Discussion
 References
 
Study Population
Male PD patients visiting the outpatient clinic of the Kyushu University Beppu Advanced Medical Center from April 2002 through March 2005 were enrolled, and some of their male family members and some of our hospital's healthy male workers, who never smoked and passed a regular medical check-up within a year before the enrollment, were also enrolled as the normal controls. The present research was performed, following the approval by the Conjoint Health Research Ethics Board of Kyushu University, and written consent was obtained from all the participants. DNA samples were obtained from peripheral leukocytes of 28 de novo male PD patients diagnosed according to the Japan Parkinson's Disease Society Brain Bank criteria. The participants ranged in age from 47 to 69 years. In terms of disease severity, all the PD patients were classified into stage 1 or stage 2 of the Hoehn–Yahr classification. Blood samples were collected from the patients before administration of anti-Parkinson agents started. Blood samples were drawn, using heparinized syringes and 10 mL Vacutainer tubes and were stratified into 10-year age groups. We added >20 times the volume of 10 mM Tris-HCl, 1 mM EDTA (pH 8.0) to the blood sample to remove erythrocytes by lowering osmotic pressure. Next, peripheral leukocytes were collected by centrifugation. To lessen the substantial confounding effects of sex, smoking, and ethnicity on telomere length, all participants were Japanese men and were never smokers. The participants were similar regarding family income, level of physical activity, and socioeconomic status. In addition, 27 healthy control participants were enrolled, matched for gender and lifestyle.

Telomeric Length Measurement
The telomeric length was measured as previously described (3,6,22). Briefly, genomic DNA was extracted from peripheral leukocyte specimens using PureGene DNA Extraction Kits (Gentra Systems, Minneapolis, MN), and the quality was assessed by agarose gel electrophoresis. Aliquots of DNA (1 µg) were used for a conventional Southern blot hybridization analysis, using a 500-bp-long (TTAGGG)n digoxigenin-labeled probe specific for telomeric repeats. The telomeric repeat probe used here is ~500 bp long (this length is much longer than that of conventional oligonucleotide telomere probes commonly used). This long probe yields dense signals and enables one to clearly detect telomeres shorter than 4.4 kb according to a Southern blot analysis (Figure 1). The blotted membranes were incubated with anti-digoxigenin-alkaline phosphatase-specific antibody. The telomere probe was visualized by CSPD (C18H20ClO7PNa2) (Boehringer Mannheim GmbH, Mannheim, Germany). The membrane was then exposed to Fuji XR film with an intensifying screen (FUJIFILM Corporation, Tokyo, Japan). The smears of the autoradiogram were captured on an Image Master (Trioptics Japan, Shizuoka), and then the telomere length was quantitatively assessed (Figure 1). Each Southern blot experiment was repeated twice, and the mean value was used. Age and mTRF of all participants are shown in Table 1.


Figure 01
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  		Figure 1. Smear pattern of a telomere Southern blot of genomic DNA from peripheral leukocytes and its densitometric analysis. Molecular weight standards are HindIII-digested {lambda} phage DNA. Each telomere smear was divided into four regions according to a molecular weight marker 23.1–9.4, 9.4–6.6, 6.6–4.4, 4.4–2.3 kb. Vertical line, densitometric scanning line. Densitometry is shown in at right.

 

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  		Table 1. Age and Mean Terminal Restriction Fragment (mTRF) of Controls and Parkinson's Disease Patients.

 
TRF Analysis
Cherif and coworkers (22) and Hemann and colleagues (23) showed that a loss of a few hundred base pairs from short telomeres could have an important affect on cellular aging but may not be detected by traditional mTRF analyses. In this study, the telomere length was therefore compared using a telomere percentage analysis with four intervals of length defined by molecular weight standards. This method has previously been used to determine the change of telomeres in rats (22). In the present study, this method was applied to determine the change of telomere length distribution in human leukocytes. In brief, the intensity of photo-stimulated luminescence (PSL) was quantified as follows: Each telomeric sample was divided into grid squares according to the molecular size ranges: 23.1 ≥ 23.1–9.4 > 9.4, 9.4 ≥ 9.4–6.6 > 6.6, 6.6 ≥ 6.6–4.4 > 4.4, and 4.4 ≥ 4.4–2.3 > 2.3 kb. The percentage of PSL in each molecular weight range was measured (%PSL = intensity of a defined region – background x 100/total lane intensity – background). The mTRF was estimated using the formula {Sigma}(ODi – background)/{Sigma}(ODi – background/Li) (24), where ODi is the chemiluminescent signal and Li is the length of the TRF fragment at position i.

Statistical Analysis
The normality of the data was examined with the Kolmogorov–Smirnov test and the homogeneity of variance with the Levene Median test. If both the normal distribution and equal variance tests were passed, the differences in the telomeres length including the mTRF length and the telomere percentage analysis with age and condition (PD patients or age-matched healthy controls) were studied using a two-way analysis of variance (ANOVA) test followed by all pairwise multiple comparison procedures using Tukey's post hoc test.

The data are expressed as the mean ± standard deviation. The criterion for the significance is p <.05. All analyses were carried out using a Sigma Statistical Analysis software package (Sigma 2.03, 2001; St. Louis, MO).


   RESULTS
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 Results
Discussion
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Correlation Between mTRF and Aging in PD Patients and Controls
mTRFs were compared between the PD patients and the age-matched controls. Telomere shortening with aging was observed both in the PD groups and the age-matched controls; telomere shortening rate of the PD patients (–131 bp/year) seemed to be faster than that of the controls (–52.4 bp/year) (Figure 2). However, no statistically significant mTRF difference was detected between the 50s and the 60s both in the PD patients and in the controls , although mTRF of the PD patients apparently seemed to be longer in patients in their 50s and shorter in those in their 60s than that of the normal controls (Table 2). However, mTRF shorter than 5 kb was only observed in the PD patients. mTRFs of the controls were always longer than 5 kb in all age ranges in this study. This finding is compatible with those of previous reports, which showed that mTRF of peripheral leukocytes of the normal population is always longer than 5 kb age independently (25,26). These short telomeres (<5 kb) implied an aspect of PD condition associated with an over-shortening of the telomere length.


Figure 02
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  		Figure 2. Correlations between the mean terminal restriction fragment (TRF) and age in normal controls and Parkinson's disease (PD) patients. The regression line in black and that in gray represent telomere shortening in the PD patients and the normal controls, respectively. Note that two PD patients in their 60s reveal short mean TRF (<5 kb)

 

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  		Table 2. Statistical Analyses of Age and Mean Terminal Restriction Fragment (mTRF) of Controls and Parkinson's Disease Patients.

 
Difference of Telomere Length Distribution with Aging Between PD Patients and Age-Matched Healthy Controls
Some significant telomere length differences with aging between the PD patients and the controls were detected in the telomere percentage analysis. A significant age-related change in telomere length in the 23.1–9.4 kb range was observed only in the PD patients (Figure 3). The significant increase in the percentage in the 9.4–6.6 kb range in the PD patients in comparison to the controls was observed in patients in their 60s. There was a significant decrease in the percentage of telomeres measuring 4.4–2.3 kb in the PD patients in comparison to the decrease in that of the controls (this is observed in participants in their 50s but not in their 60s) (Figure 3). This finding indicated that the longest telomeres (23.1–9.4 kb) were decreasing in the PD patients, but not in the controls during their 50s and 60s (28.8 ± 1.9 to 21.4 ± 1.4, p <.01). The decrease of the number of telomeres in the 23.1–9.4 kb range seemed to be accelerated in the PD patients from their 50s to their 60s. The significant increase of telomeres in the 9.4–6.6 kb range in the PD patients in their 60s in comparison to the controls may correspond to the significant decrease in the number of the longest telomeres (23.1–9.4 kb) in patients from their 50s to 60s (Figure 3). The same kind of telomere length change was reported in our previous study about aging-associated telomere length change in a Japanese healthy population. The telomeres longer than 9.4 kb were decreasing faster in men than in women (from their 20s to 30s), and a corresponding relative increase of the second longest (9.4–6.6 kb) telomeres was observed in men in comparison to women (5).


Figure 03
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  		Figure 3. A comparison of the telomere length between Parkinson's disease (PD) patients and age-matched controls using telomere length percentage analysis. Each telomere smear was divided into four regions according to molecular weight markers (23.1–9.4, 9.4–6.6, 6.6–4.4, and 4.4–2.3 kb). White and gray columns, respectively, represent the percentage of each telomere length range indicated by the normal controls and the PD patients. Data are the mean ± standard deviation

 
The percentage of the shortest range of telomere (4.4–2.3 kb) was significantly lower in the PD patients than in the controls, especially in persons in their 50s, and the statistical difference disappeared in their 60s. These findings indicate that long telomeres are decreasing and short telomeres are increasing with aging, and these events occur more rapidly in PD, thus suggesting that telomere shortening is more rapid in PD patients during their 50s and 60s compared to the normal population. From our results, the telomere percentage analysis method also turned out to be a more sensitive method in detecting telomeric length changes with aging in PD than was the mTRF analysis.


   DISCUSSION
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 Materials and Methods
 Results
 Discussion
References
 
To our knowledge, this is the first study about telomere length changes in PD patients. From the comparison of the correlation of mTRF regression and aging between the PD patients and the normal controls shown in Figure 2, the mTRF decrease was seemingly faster in PD than in the controls. The accelerated telomere shortening was not confirmed by analysis of mTRF but by that of telomere length distribution in the PD patients and the controls. The significant differences in the telomere length percentage profile confirmed a tendency of an acceleration of telomere length shortening in the PD patients in the mTRF analysis. It is concluded from these results of mTRF and the telomere length percentage profiles that telomere shortening was accelerated in PD patients from their 50s to their 60s, compared to controls. It has been reported that telomeres of peripheral leukocytes are shortened with aging, and the shortening is accelerated by various disease conditions (5,11,12,16,17,22,24,27). The aging-related telomere shortening accompanies a decrease in the number of longest-range telomeres (23.1–9.4 kb) and an increase in the number of telomeres shorter than 4.4 kb. In this context, a lower percentage of the telomeres shorter than 4.4 kb represents a younger pattern of telomere length distribution of peripheral blood leukocytes. The observed pattern of the telomere length distribution in the PD patients in their 50s appeared to be a younger pattern of the controls. However, the increase in the number of shorter telomeres was accelerated from the 50s to the 60s in PD patients. The PD patients in their 50s seem to bear a telomere length distribution pattern that looks like a pattern of a younger person, but reveal more rapid telomere shortening after that, supported by the decrease in the number of long telomeres (23.1–9.4 kb) and the increase in the number of short telomeres (4.4–2.3 kb), compared to controls. These results suggested that the acceleration of telomere shortening was associated with PD condition rather than was mTRF itself. Telomeres shorter than 5 kb were not observed in the controls. These short telomeres can also be regarded as a result of the enhanced telomere shortening in PD. Recent human and animal studies indicate that oxidative stress and neuroinflammation are related to the etiopathogenesis of PD (3–5,9,17,19,26–32).

Enhanced oxidative DNA damage in peripheral blood cells of PD patients has been reported (17,32–34). The increased sensitivity to oxidative stress may be associated with provoking neuroinflammation (35,36) as a possible predisposition for PD. These observations can be reflected in the telomere length alteration in PD described in the present study. Enhanced oxidative stress and neuroinflammation can induce acceleration of telomere shortening as a predisposing factor for the etiopathogenesis of PD. The accelerated shortening of the telomeres and the presence of an mTRF shorter than 5 kb in the PD patients can be caused by increasing oxidative stress with neuroinflammation. The present findings suggest that the telomere length study in peripheral leukocytes in patients can reflect an instructive and representative change in PD. The pathogenetic process of PD is active for a long time prior to the diagnosis of PD, and the long period of inflammation and oxidative damage may cause a chronic enhancement of leukocyte turnover. However, the present study indicates that PD condition is associated not with shortened mTRF but with acceleration of telomere shortening. The PD-pathogenetic affects do not appear on a telomere length profile at least until a person is in his or her 50s. PD symptoms seem to become overt when the PD pathogenesis-associated effects appear as an acceleration of telomere shortening. It seems that accumulated oxidative stress for PD pathogenesis has no effect on telomere shortening before the 50s and yields PD symptoms and telomere erosion thereafter. Strangely, the percentage of the shortest range of telomeres (4.4–2.3 kb) in the 50s was lower in the PD patients than in the controls. We cannot explain the younger pattern of telomere length distribution in PD patients in their 50s in association with PD pathogenesis, so far. The onset of PD seems to relate to an increased telomere shortening rate but not to telomere length shortness. The PD symptoms would appear after a long disease-predisposing period, during which oxidative stress or neuroinflammation might have chronic harmful effects on the brain parenchyma and telomere shortening of peripheral leukocytes became accelerated to an extent. Although many studies have shown that various pathophysiological conditions are associated with the shortening of mTRF in human blood cells, there was no difference in the mTRF length between the PD patients and the controls. However, there were some significant differences in telomere-length distribution observed based on a telomere length percentage analysis. This observation indicates that pathological telomeric status is not detectable by a simple analysis of the mean telomere length in some diseases, including PD. The onset of symptoms of diseases like PD may appear after the acceleration of telomere shortening starts. It is unclear why PD onset is not associated with the shortness of telomere size but with the accelerated rate of shortening of the telomere. Large-scale, long-term cohort studies of the normal population will elucidate how the acceleration of telomere shortening and the onset of chronic diseases like PD are associated. Further study is also necessary to clarify whether anti-Parkinson agents can prevent the acceleration of telomere shortening.


   Acknowledgments
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This work was supported, in part, by a Grant-in-Aid from the Ministry of Education, Science, and Culture of Japan and by a Grant-in-Aid from Chiyoda Mutual Life Foundation.

We thank Ms. Yasuko Ueda and Ms. Sachiyo Taguchi for their valuable technical assistance. We also thank Dr. Brian Quinn for linguistic advice.

Tomokazu Suzuki is now with Kinki Central Hospital, Itami-city, Hyogo, Japan.

Drs. Guan and Maeda contributed equally to the preparation of this manuscript.


   Footnotes
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Decision Editor: Huber R. Warner, PhD

Received July 3, 2007

Accepted December 26, 2007


   References
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