Proteasome inhibitor model of Parkinson's disease in mice is confounded by neurotoxicity of the ethanol vehicle

Abstract

Defects in the ubiquitin-proteasome system have been implicated in Parkinson's Disease (PD). Recently, a rat model of PD was developed using a synthetic proteasome inhibitor (PSI), (Z-lle-Glu(OtBu)-Ala-Leu-al). We attempted to transfer this model to mouse studies, where genetics can be more readily investigated due to the availability of genetically modified mice. We treated C57BL/6 (B6) mice with six intraperitoneal injections of 6 mg/kg PSI in 50 mul of 70% ethanol over a 2-week-period. We found significant decreases in nigrostriatal dopamine in PSI-treated mice compared with saline-treated mice. However, we observed similar decreases in the ethanol-treated vehicle control group. Administration of ethanol alone led to significant long-term alterations in dopamine levels. Ethanol significantly eclipses the effects of PSI in the dopamine system, and therefore is a confounding vehicle for this model.

Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human α-synuclein under oligodendrocyte promoter: implications for multiple system atrophy

“…Systemic application of proteasome inhibitors has failed to cause any detectable behavioral or neuropathological abnormalities relevant to PD in mice [4, 19, 36]. In agreement with these findings we did not observe signs of motor deterioration and neuronal loss in striatonigral and olivopontocerebellar structures upon systemic PSI treatment in wild-type mice.…”

“…The PSI groups received proteasome inhibitor I (Z-Ile-Glu(OtBu)-Ala-Leu-CHO), a cell-permeable reversible inhibitor of the chymotrypsin-like activity of the 20S proteasome, provided in 50 mM stock solution in DMSO (Calbiochem, La Jolla, CA). PSI was applied subcutaneously every other day over a period of 2 weeks at a concentration of 5 mg per kilo body weight per day in 1.7 % DMSO in saline as based on previous protocols and data [4, 13, 19, 22, 34, 36, 46]. The vehicle-treated groups received 1.7 % DMSO in saline according to the same time schedule.…”

Morphological and Metabolic Changes in the Nigro-Striatal Pathway of Synthetic Proteasome Inhibitor (PSI)-Treated Rats: A MRI and MRS Study

“…Nevertheless, the concept of abnormal protein aggregation is still the focus of research on PD [10], and, even though cautious conclusions are demanded, we believe that PSI based models can unveil unexplored aspects of SN pathophysiology, as the publications of recent works, using PSI in combination with other compounds by different laboratories seem to confirm [11]–[12].…”

Alcohol drinking and risk of Parkinson's disease: a case-control study in Japan

“…Ethanol enhanced the toxicity of 6-hydroxydopamin (6-OHDA) when ethanol and 6-OHDA were simultaneously applied to cultured cells [20]. In an attempt to create a mouse version of the rat model of PD, developed using a synthetic proteasome inhibitor (PSI), decreased levels of nigrostriatal dopamine were observed both in the mice treated with PSI in an ethanol-vehicle and in control mice with ethanol-vehicle alone [21]. By contrast, it was reported that ADHs, and not ALDHs, play important roles in the synthesis of retinoic acid, which may influence the proper development and maintenance of the dopaminergic system [32].…”

“…It has been reported that those with flushing responses drank significantly less hard liquor than those without [19]. Because aldehydes may react with dopamine both in vitro and in vivo [20,21], it might be hypothesized that relations between alcohol and PD risk vary according to flushing status. To our knowledge, only one study, a case-control study from Japan, investigated a possible effect modification by ALDH2 activity and found that average alcohol consumption was significantly lower among cases than controls regardless of ALDH2 genotype [3].…”