Cancer Treatment-Related Fatigue Is Associated With Alpha-Synuclein Overexpression

Purpose: To explore the relationship between alpha-synuclein gene and protein expression with fatigue symptoms in men with prostate cancer receiving external beam radiation therapy (EBRT).

Background:                                                                                                                                                                                                                                                                               1. Up to 99% of cancer patients experience fatigue during their treatments.¹                                                                                                                             2. Scant evidence show that genetic factors, energy expenditure, metabolism, aerobic capacity, and immune responses are involved in cancer-related fatigue (CRF).^2,3                                                                                                                                                                                                                                3. mRNA expression changes of various DNA repair genes were noted from peripheral blood monocytes of cancer patients, who developed radiation-related fatigue.⁴

Methods:  Revised Piper Fatigue Scale (rPFS) and blood samples collected at baseline prior to EBRT; 24 hours, 7 days, 14 days, midpoint, at completion of EBRT and 30 days post EBRT. Baseline data were compared with gender, age, and race-matched healthy controls. Microarray gene expression: Affymetrix HG U133 plus 2.0 gene chips were used. The fold change for each patient between healthy controls and pre-EBRT and between pre-EBRT to the seven timepoints were calculated. Principal component analyses was conducted on all gene chips. Outliers were excluded from  linear regression analyses using time as the continuous variable. Genes were selected using a false discovery rate of 1% and a slope of 0.07 or more.

Results: Fatigue scores changed significantly overtime during EBRT compared at baseline (pre-EBRT) (p<.00001) from a linear mixed effect model analysis. α-synuclein gene expression was significantly correlated with fatigue (R = -.90, p<0.006) while α-synuclein protein expression and fatigue scores trended towards significance (R=-.72, p=0.07).

Discussion: In this population, development or worsening of fatigue may be related to α-synuclein’s role in mitochondrial function and its involvement in the inflammatory response to initial stress. α-synuclein is known to cause mitochondrial dysfunction leading to neurodegeneration as observed in many behavioral conditions. In this study, it is believed that α-synuclein expression is induced as part of the physiological response to EBRT. Further investigation is needed to explore the role α-synuclein overexpression during a physiological response to stress in the development or worsening of fatigue symptoms.

Implications: The study findings may provide hints to potential etiologic mechanisms for CRF. α-synuclein together with other differentially expressed genes identified in this study may serve as therapeutic targets for CRF.

References:                                                                                                                                                                                                                                                                                             1. Goedendorp MM, Gielissen MF, Verhagen CA, Peters ME, Bleijenberg G      (2008) Severe fatigue and related factors in cancer patients before the initiation of treatment. Br J Cancer99:1408-14.                                                                                                                                                              2.Mandelker L. Introduction to oxidative stress and mitochondrial dysfunction. Vet Clin North Am Small Anim Pract. Jan 2008;38(1):1-30.      3.Greenberg DB, Gray JL, Mannix CM, Eisenthal S, Carey M. Treatment-related fatigue and serum interleukin-1 levels in patients during external beam irradiation for prostate cancer. J Pain Symptom Manage 1993 May;8(4):196-200.                                                                                                             4.Sonis S, Haddad R, Posner M, et al. (2007) Gene expression changes in peripheral blood cells provide insight into the biological mechanisms associated with regimen-related toxicities in patients being treated for head and neck cancers. Oral Oncology 43:289-300.

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