Changes in Selenoprotein P in Substantia Nigra and Putamen in Parkinson's Disease

Abstract

Oxidative stress and oxidized dopamine contribute to the degeneration of the nigrostriatal pathway in Parkinson’s disease (PD). Selenoproteins are a family of proteins containing the element selenium in the form of the amino acid selenocysteine, and many of these proteins have antioxidant functions. We recently reported changes in expression of the selenoprotein, phospholipid hydroperoxide glutathione peroxidase GPX4 and its co-localization with neuromelanin in PD brain. To further understand the changes in GPX4 in PD, we examine here the expression of the selenium transport protein selenoprotein P (Sepp1) in postmortem Parkinson’s brain tissue. Sepp1 in midbrain was expressed in neurons of the substantia nigra (SN), and expression was concentrated within the centers of Lewy bodies, the pathological hallmark of PD. As with GPX4, Sepp1 expression was significantly reduced in SN from PD subjects compared with controls, but increased relative to cell density. In putamen, Sepp1 was found in cell bodies and in dopaminergic axons and terminals, although levels of Sepp1 were not altered in PD subjects compared to controls. Expression levels of Sepp1 and GPX4 correlated strongly in the putamen of control subjects but not in the putamen of PD subjects. These findings indicate a role for Sepp1 in the nigrostriatal pathway, and suggest that local release of Sepp1 in striatum may be important for signaling and/or synthesis of other selenoproteins such as GPX4.

Cerebrospinal fluid of newly diagnosed amyotrophic lateral sclerosis patients exhibits abnormal levels of selenium species including elevated selenite

“…Recent animal and human studies investigating the relation of SePP with neurological or other diseases have yielded sharply different results (Bellinger et al, 2008; Yang et al, 2011; Bellinger et al, 2012; Raman et al, 2012; Takata et al, 2012), not unexpectedly in selenium research, making it difficult to assess the biological significance of our findings. The hypothetical role of SePP in CNS diseases is intriguing and controversial, ranging from beneficial as suggested by animal studies (Raman et al, 2012) to potentially deleterious in human neurodegenerative diseases (Bellinger et al, 2008; Bellinger et al, 2012).…”

“…The hypothetical role of SePP in CNS diseases is intriguing and controversial, ranging from beneficial as suggested by animal studies (Raman et al, 2012) to potentially deleterious in human neurodegenerative diseases (Bellinger et al, 2008; Bellinger et al, 2012). Scharpf et al .…”

Glutathione metabolism and Parkinson's disease

“…Further study of Selenoprotein 1 (Sepp1, a transport protein and source of selenium for selenoproteins) and GPX4 in the SN and putamen shows an association between Sepp1 and GPX4 localization in the putamen of control subjects while the correlation is lost in PD patients. No correlation of Sepp1 and GPX4 immunoreactivity is seen in the SN of PD or control samples [117]. …”

Selenium and selenoprotein function in brain disorders

“…This may be due to greater selenium utilization for selenoprotein production in the brain, possibly for preventing further oxidative damage. Although Sepp1 is decreased in the SN of postmortem PD brain, accounting for cell loss reveals that Sepp1 is increased relative to the density of surviving SN neurons . Sepp1 also colocalizes with presynaptic terminals in the striatum.…”

“…Thus, Sepp1 is important for Se retention within the brain. Changes in Sepp1 may be involved in neurodegenerative disorders such as Alzheimer's and Parkinson's .…”