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. 2013 Jan;27(1):63-70.
doi: 10.1016/j.bbi.2012.09.009. Epub 2012 Sep 26.

Upregulation of α-synuclein during localized radiation therapy signals the association of cancer-related fatigue with the activation of inflammatory and neuroprotective pathways

L N Saligan  1 , C P Hsiao, D Wang, X M Wang, L St John, A Kaushal, D Citrin, J J Barb, P J Munson, R A Dionne
Affiliations

Upregulation of α-synuclein during localized radiation therapy signals the association of cancer-related fatigue with the activation of inflammatory and neuroprotective pathways

L N Saligan et al. Brain Behav Immun. 2013 Jan.

Abstract

Purpose: Neuroinflammatory mechanisms are associated with fatigue in neurodegenerative conditions such as Parkinson's. The symptoms in Parkinson's including fatigue are thought to be related to α-synuclein overexpression. This study investigated genomic correlates of fatigue experienced by men with prostate cancer receiving external beam radiation therapy (EBRT).

Patients and methods: Sixteen men with non-metastatic prostate cancer who were scheduled to receive EBRT were enrolled. Fatigue scores and blood were obtained at baseline (prior to EBRT, D0); one hour following initiation of EBRT (D1), day 7 (D7), day 14 (D14), midpoint (days 19-21, D21), completion (days 38-42, D42), and four weeks post-EBRT (days 68-72, D72). Gene expression profiling using microarray analysis was performed from peripheral blood and confirmatory qPCR and protein (ELISA) analyses verified the microarray results. Correlations between fatigue and gene/protein expressions were determined using a mixed model approach.

Results: Microarray data showed significant, differential expression of 463 probesets following EBRT. SNCA had a 2.95-fold change at D21 from baseline. SNCA expression was confirmed by qPCR (p<0.001) and ELISA (p<0.001) over time during EBRT. Fatigue scores were significantly correlated with SNCA gene expression on D14 (r=0.55, p<0.05) and plasma α-synuclein concentrations on D42 of EBRT (r=0.54, p=0.04).

Conclusion: Fatigue experienced during EBRT may be mediated by α-synuclein overexpression. Alpha-synuclein may serve as a useful biomarker to understand the mechanisms and pathways related to the development of fatigue in this population.

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Figures

Figure 1
Figure 1. Expression of SNCA gene during EBRT by microarray
SNCA = alpha-synuclein gene, EBRT = external beam radiation therapy
Figure 2
Figure 2. SNCA expression during EBRT as confirmed by qPCR
SNCA = alpha-synuclein gene, EBRT = external beam radiation therapy, ΔCt = delta cycle time (an approximation method), qPCR = quantitative polymerase chain reaction
Figure 3
Figure 3. Alpha-synuclein plasma concentration during EBRT
ng/ml = nanogram per milliliter, EBRT = external beam radiation therapy
Figure 4
Figure 4. Fatigue scores during EBRT
EBRT = external beam radiation therapy. Fatigue was measured using the revised Piper Fatigue Scale.
Figure 5
Figure 5. Correlation between fatigue and α-synuclein expression
The changes of fatigue and gene/protein expressions were modeled in a linear fashion. The intercept of the individual growth curve represents the estimated baseline (D0) value for each patient based on a linear trajectory of the values over time during EBRT. The slope of the individual growth curve represents the estimated rate of change over time for each patient based on a linear trajectory of their scores. The intercepts and slopes of fatigue scores were estimated based on mixed model for each patient and the resulting estimated intercepts and slopes were then correlated. Figure 5a. Correlation between fatigue and SNCA qPCR expression intercepts. SNCA = alpha-synuclein gene; qPCR = quantitative polymerase chain reaction Figure 5b. Correlation between fatigue and SNCA qPCR expression slopes. SNCA = alpha-synuclein gene; qPCR = quantitative polymerase chain reaction Figure 5c. Correlation between fatigue and α-synuclein protein intercepts. Figure 5d. Correlation between fatigue intercept and α-synuclein protein slope.
Figure 6
Figure 6. Effect of prostate cell irradiation on α-synuclein expression
ng = nanogram, ml = milliliter, two doses of radiation used = 1 Gray (GY1) and 2 Gray (GY2)
See this image and copyright information in PMC

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