Neurology -- Correspondence for Blandini et al., 66 (4) 529-534

Correspondence published:

Peripheral proteasome and caspase activity in Parkinson disease and Alzheimer disease: Jeff M Bronstein, Arthur P. Chou (18 April 2006)

Reply from the Author: Fabio Blandini (18 April 2006)

Peripheral proteasome and caspase activity in Parkinson disease and Alzheimer disease 18 April 2006

Jeff M Bronstein,
UCLA School of Medicine
Department of Neurology, 710 Westwood Plaza, Los Angeles, CA 90095,
Arthur P. Chou
Send Correspondence to journal:
Re: Peripheral proteasome and caspase activity in Parkinson disease and Alzheimer disease

jbronste{at}ucla.edu Jeff M Bronstein, et al.

We read with great interest the article by Blandini et al. [1] They reported reduced 20S proteasome activity in peripheral blood lymphocytes (PBLs) in patients with Parkinson’s disease (PD).
Their data demonstrated a reduction in 20S proteasome activity only in patients treated with L-dopa and dopamine agonist (DA) but not in untreated patients. They also reported a correlation between disease duration to a reduction of 20S proteasome activity and concluded that this correlation “points to the progression of the disease rather than to the pharmacologic treatment as a factor capable of influencing proteasome 20S activity in PBLs of PD patients”.
It would seem more plausible that the reduction in 20S activity is completely due to the drug treatment and not the disease. Was there a correlation between disease duration and total dose of medication? This would be expected since most PD patients take more medication as the disease progresses. If this were the case, then we would expect to see a dose response between medication and 20S activity adding support to a drug effect and not disease duration effect.
Biologically, a plausible hypothesis is that proteasome activity in a peripheral tissue represents an inherent alteration in proteasome function in the brain (i.e. a peripheral biomarker) that contributed to the pathogenesis of PD. If this were the case, 20S activity would not change in PBLs with disease progression as Blandini et al proposed.
If PD medications do cause a reduction in proteasome activity in PBLs, this may have important implications. As the authors stated, proteasome inhibitors can cause cell death in cell models [2] and recreate many of the clinical and pathological correlates of PD in rodents. [3] Blandini et al’s data would suggest that L-dopa and DA therapy lowers 20S activity in PBLs and possibly in neurons. Could medication be contributing to disease progression?
References
1. Blandini F, Sinforiani E, Pacchetti C, et al. Peripheral proteasome and caspase activity in Parkinson disease and Alzheimer disease. Neurology 2006;66:529-534.
2. McNaught KS, Mytilineou C, Jnobaptiste R, et al. Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures. J Neurochem 2002;81:301-306.
3. McNaught KS, Perl DP, Brownell AL, Olanow CW. Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease. Ann Neurol 2004;56:149-162.
Disclosure: The authors report no conflicts of interest.

Reply from the Author 18 April 2006

Fabio Blandini,
IRCCS Neurological Institute “C. Mondino”
Via Mondino, 2 - 27100 Pavia, Italy
Send Correspondence to journal:
Re: Reply from the Author

fabio.blandini{at}mondino.it Fabio Blandini

We thank Bronstein and Chou for their interest in our article. They raise an important question: Was it the disease progression or the pharmacological treatment that influenced proteasome 20S levels in our PD patients?
When we separately analyzed patients under monotherapy with L-Dopa and patients treated with L-Dopa plus DA-agonists, we found that patients under monotherapy had levels of proteasome 20S activity (1.8 +/- 0.3 nmol) similar to those seen in controls (2.3 +/- 0.2 nmol; p=0.28). We concluded that the difference between treated PD patients and the other groups was ascribable to the subgroup of patients taking both L-Dopa and DA-agonists, who were also those with the longest disease duration.
Based on our results and the assumption that the reduction in proteasome activity was due to the pharmacological treatment, it could also be assumed that DA-agonists were solely responsible. In our opinion, such a conclusion cannot be drawn without further investigation particularly when we consider the bulk of data suggesting a neuroprotective effect for this class of compounds. [4,5]
Moreover, we did not find a significant correlation between disease duration and total dose of medication (r=0.19; p=0.31). However, high levels of dopamine represent a favorable condition for a defective regulation of proteasomal activity and possibly the formation of intracellular inclusions. [6,7] For this reason, we are now testing the effects of dopamine on proteasome 20S and caspase activity in isolated human lymphocytes from normal subjects. Preliminary results seem to indicate a dose-dependent, inhibitory effect of dopamine on proteasomal activity. If confirmed, the hypothesis of a pharmacological origin for the proteasome 20S deficiency found in treated PD patients would be further supported.
Regarding the concept that a central, biochemical defect may play a causative and constant role is doubtful considering the progressive nature of PD. Neurochemical, neuroanatomical, electrophysiological changes accompany the evolution of the disease. Recently it has been demonstrated in a rodent model that with chronic MPTP administration, MPTP- induced proteasomal impairment evolves with time. [8]
References
4. Schapira AH. Neuroprotection and dopamine agonists. Neurology 2002; 58(4 Suppl 1):S9-18.
5. Marek K, Jennings D, Seibyl J. Dopamine agonists and Parkinson's disease progression: what can we learn from neuroimaging studies. Ann Neurol 2003; 53 Suppl 3:S160-S166.
6. Keller JN, Huang FF, Dimayuga ER, Maragos WF. Dopamine induces proteasome inhibition in neural PC12 cell line. Free Radic Biol Med 2000; 29:1037-1042.
7. Yoshimoto Y, Nakaso K, Nakashima K. L-dopa and dopamine enhance the formation of aggregates under proteasome inhibition in PC12 cells. FEBS Lett 2005; 579:1197-1202.
8. Fornai F, Schluter OM, Lenzi P, et al. Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc Natl Acad Sci U S A 2005; 102:3413-3418.
Disclosure: The author reports no conflicts of interest.