Quantitative Profiling and Identification of Plasma Proteins of Spinocerebellar Ataxia Type 2 Patients

Abstract

Background: Spinocerebellar ataxia type 2 (SCA2) is an autosomal-dominant hereditary ataxia characterized by progressive gait and limb ataxia, dysarthria, slow saccades, neuropathy and dementia. The expansion of trinucleotide CAG repeats in the coding region of the ATXN-2 gene leads to expanded polyglutamine stretch in the mutated protein which causes neuronal death. Objective: In this study, we investigated the blood plasma of SCA2 patients to find protein biomarkers. Methods: Thirty-two ataxia patients clinically suspected for SCA2 were evaluated by the International Co-operative Ataxia Rating Scale followed by genetic analysis using PCR. Plasma proteomics of SCA2 patients and age- and gender-matched healthy controls was done using 2D-difference in-gel electrophoresis, LC-MS/MS and Western blot. Results: Genetic analysis confirmed 10 of 32 suspected SCA2 patients. Proteomic data revealed nine differentially expressed proteins in SCA2. These proteins find good association with oxidative stress, calcium-dependent apoptosis, neuropathy, and cognitive impairment in SCA2 patients. Interestingly, the elevated levels of the voltage-dependent calcium channel γ-3 subunit showed a direct correlation with calcium-generated apoptosis of Purkinje cells. The cognitive deficit, a common symptom in SCA2 patients, seems to correlate with decreased levels of transthyretin and retinol-binding protein-4. Conclusions: Some of these identified proteins in SCA2 can be useful for therapeutic, diagnostic and prognostic purposes.

Quantitative profiling and identification of differentially expressed plasma proteins in friedreich's ataxia

“…3A,B). Earlier reports on dysregulated lipid metabolism in a number of neurodegenerative diseases, including Alzheimer's, Parkinson's, Niemann-Pick's, and Huntington's diseases (Adibhatla and Hatcher, 2008); spinocerebellar ataxia type 12 (Swarup et al, 2012); and spinocerebellar ataxia type 2 (Swarup et al, 2013), support the present observations found in FRDA. Low levels of apoC-II and C-III obtained in plasma of FRDA patients in our study indicate their possible role in altered lipid metabolism among FRDA patients.…”

Evidence of oxidative stress and mitochondrial dysfunction in spinocerebellar ataxia type 2 (SCA2) patient fibroblasts: Effect of coenzyme Q10 supplementation on these parameters

“…A recent proteomic study on SCA2 patient blood plasma showed a large increase in the apolipoprotein E (ApoE) protein level (Swarup et al, 2013). In addition to being involved in lipid and cholesterol transport and metabolism, ApoE has previously been shown to be protective against oxidative damage by ROS such as H2O2, which we see increased in our SCA2 patient cells (Miyata & Smith, 1996;Tangirala et al, 2001).…”

“…SCA2 has been suggested to be linked to oxidative stress, yet the source of oxidative stress in patients is not well characterized (Almaguer-Gotay et al, 2014;Swarup et al, 2013). In this study we investigated the level of mitochondrial oxidative stress by assessing superoxide levels in fibroblasts from SCA2 patients and controls.…”

“…It has been hypothesized that ApoE is an amyloid catalyst or "pathological chaperone" (Bales et al, 1999;Ma, Yee, Brewer, Das, & Potter, 1994;Wisniewski, Castaño, Golabek, Vogel, & Frangione, 1994), and it has been posited that ApoE regulates Aβ clearance (Castellano et al, 2011;Cramer et al, 2012;Jiang et al, 2008). Notably, it has previously been shown that ApoE is increased in serum of SCA2 patients (Swarup et al, 2013). Consistent with this finding we found markedly increased levels of ApoE mRNA and protein in SCA2 patient fibroblasts compared to controls, and this difference was reversed upon treatment with CoQ10.…”

“…Huntington disease (HD) (Federico et al, 2012), and although the mechanisms responsible for development of these diseases are not fully resolved, it seems clear that oxidative stress plays an important role. Furthermore, altered activity of key antioxidant enzymes and markers of increased apoptosis have been found in serum of SCA2 patients (Almaguer-Gotay et al, 2014;Swarup, Srivastava, Padma, & Moganty, 2013). However, there are few studies on oxidative stress in SCA2 and more are needed to understand the underlying mechanisms.…”