Striatal Proteomic Analysis Suggests that First L-Dopa Dose Equates to Chronic Exposure

Scholz, Birger; Svensson, Marcus; Alm, Henrik; Sköld, K.; Fälth, Maria; Kultima, Kim; Guigoni, Céline; Doudnikoff, Évelyne; Li, Qin; Crossman, Alan R.; Bézard, Erwan; Andrén, Per E.

doi:10.1371/journal.pone.0001589

Cited by 48 publications

(37 citation statements)

References 57 publications

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“…These observations were supported by quantitative immunoelectron microscopy data from 6-OHDA-treated rats showing a significant decrease in the number of striatal D1-negative spines (Day et al, 2006). A recent electron microscopy study using a non-stereologic spine count method showed a relative decrease in the number of D2-immunopositive spines accompanied with an increase in the number of D1-immunoreactive spines in a MPTP-treated monkey model of PD (Scholz et al, 2008). On the other hand, these observations are different from those in a large number of Golgi studies in both human parkinsonians and animal models of parkinsonism showing a rather homogeneous loss of spines across large populations of Golgi-impregnated striatal medium spiny neurons (Ingham et al, 1989; Stephens et al, 2005; Zaja-Milatovic et al, 2005; Villalba et al, 2009; Smith et al, 2009b).…”

Section: - Striatal Spine Pathogenesis In Parkinson’s Disease Versumentioning

confidence: 99%

Differential striatal spine pathology in Parkinson’s disease and cocaine addiction: A key role of dopamine?

Villalba

Smith

2013

Neuroscience

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In the striatum, the dendritic tree of the two main populations of projection neurons, called “Medium Spiny Neurons (MSNs)”, are covered with spines that receive glutamatergic inputs from the cerebral cortex and thalamus. In Parkinson’s disease (PD), striatal MSNs undergo an important loss of dendritic spines, whereas aberrant overgrowth of striatal spines occurs following chronic cocaine exposure. This review examines the possibility that opposite dopamine dysregulation is one of the key factors that underlies these structural changes. In PD, nigrostriatal dopamine degeneration results in a significant loss of dendritic spines in the dorsal striatum, while rodents chronically exposed to cocaine and other psychostimulants, display an increase in the density of “thin and immature” spines in the nucleus accumbens (NAc). In rodent models of PD, there is evidence that D2 dopamine receptor-containing MSNs are preferentially affected, while D1-positive cells are the main targets of increased spine density in models of addiction. However, such specificity remains to be established in primates. Although the link between the extent of striatal spine changes and the behavioral deficits associated with these disorders remains controversial, there is unequivocal evidence that glutamatergic synaptic transmission is significantly altered in both diseased conditions. Recent studies have suggested that opposite calcium-mediated regulation of the transcription factor myocyte enhancer factor 2 (MEF2) function induces these structural defects. In conclusion, there is strong evidence that dopamine is a major, but not the sole, regulator of striatal spine pathology in PD and addiction to psychostimulants. Further studies of the role of glutamate and other genes associated with spine plasticity in mediating these effects are warranted.

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Section: - Striatal Spine Pathogenesis In Parkinson’s Disease Versumentioning

confidence: 99%

Differential striatal spine pathology in Parkinson’s disease and cocaine addiction: A key role of dopamine?

Villalba

Smith

2013

Neuroscience

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“…The introduction of mass spectrometry to the field of comprehensive protein analysis, termed proteomics, has advanced the field significantly because MS offers high specificity while being relative time and cost effective. The only two proteomic studies published so far on LID and PD employed two dimensional-differential gel electrophoresis (2D-DIGE), but because of limitation concerning analysis of low molecular weight compounds (Ͻ5 kDa), gel electrophoresis based proteomic studies do not permit the analysis of endogenous neuropeptides, such as the fully processed opioid peptides (53,54). Furthermore, neuropeptide levels are often present in low amounts in the femtomolar range beyond the limits of detection of gel-based proteomics (55).…”

Section: Detection Of Other Dynorphin Related Peptides-several Dynorpmentioning

confidence: 99%

L-DOPA-induced dyskinesia is associated with regional increase of striatal dynorphin peptides as elucidated by imaging mass spectrometry

Hanrieder

Karlsson

Fälth

et al. 2011

Pharmacological Reports

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Opioid peptides are involved in various pathophysiological processes, including algesia, epilepsy, and drug dependence. A strong association between L-DOPA-induced dyskinesia (LID) and elevated prodynorphin mRNA levels has been established in both patients and in animal models of Parkinson's disease, but to date the endogenous prodynorphin peptide products have not been determined. Here, matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) was used for characterization, localization, and relative quantification of striatal neuropeptides in a rat model of LID in Parkinson's disease. MALDI IMS has the unique advantage of high sensitivity and high molecular specificity, allowing comprehensive detection of multiple molecular species in a single tissue section. Indeed, several dynorphins and enkephalins could be detected in the present study, including dynorphin A(1-8), dynorphin B, ␣-neoendorphin, MetEnkRF, MetEnkRGL, PEnk (198 -209, 219 -229). IMS analysis revealed elevated levels of dynorphin B, ␣-neoendorphin, substance P, and PEnk (220 -229) in the dorsolateral striatum of high-dyskinetic animals compared with low-dyskinetic and lesion-only control rats. Furthermore, the peak-intensities of the prodynorphin derived peptides, dynorphin B and ␣-neoendorphin, were strongly and positively correlated with LID severity. Interestingly, these LID associated dynorphin peptides are not those with high affinity to opioid receptors, but are known to bind and activate also -and ⌬-opioid receptors. In addition, the peak intensities of a novel endogenous metabolite of ␣-neoendorphin lacking the N-terminal tyrosine correlated positively with dyskinesia severity. MALDI IMS of striatal sections from Pdyn knockout mice verified the identity of fully processed dynorphin peptides and the presence of endogenous des-tyrosine ␣-neoendorphin. Des-tyrosine dynorphins display reduced opioid receptor binding and this points to possible novel nonopioid receptor mediated changes in the striatum of dyskinetic rats. Because des-tyrosine dynorphins can only be detected by mass spectrometry, as no antibodies are available, these findings highlight the importance of MALDI IMS analysis for the study of molecular dynamics in neurological diseases. Molecular & Cellular

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“…Proteomic techniques allow complex biology especially as they relate to disease processes, making it possible to unravel the basis of LID manifestation in the DA-depleted brain. To fill this void, the MPTP macaque model was used to study the proteome in DA-depleted striatum with and without subsequent acute and chronic L-dopa treatment using two-dimensional difference in-gel electrophoresis and mass spectrometry (Kultima et al , 2006; Scholz et al , 2008). Interestingly, the experimental design included control monkeys, untreated parkinsonian monkeys, parkinsonian monkeys treated for the first time ever that did not exhibit dyskinesia at the peak of the antiparkinsonian effect, and parkinsonian monkeys chronically-treated with L-dopa for months and displaying overt dyskinesia at the peak of the antiparkinsonian effect (Scholz et al , 2008).…”

Section: Pathophysiology Of Da-depleted and Daergic Drug First-evementioning

confidence: 99%

Priming for l-dopa-induced dyskinesia in Parkinson’s disease: A feature inherent to the treatment or the disease?

Nadjar

Gerfen

Bézard

2009

Progress in Neurobiology

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119

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Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa therapy for Parkinson’s disease ultimately experienced by the vast majority of patients. This article does not review the increased understanding of dyskinesia pathophysiology we have seen during the past few years but, instead, specifically focuses upon the very first molecular events thought to be responsible for the establishment of dyskinesia and generally grouped under the term of “priming”. Priming is classically defined as the process by which the brain becomes sensitized such that administration of a dopaminergic therapy modifies the response to subsequent dopaminergic treatments. In this way, over time, with repeated treatment, the chance of dopaminergic stimulation eliciting dyskinesia is increased and once dyskinesia has been established, the severity of dyskinesia increases. In this opinion review, however, we aim at strongly opposing the common view of priming. We propose, and hopefully will demonstrate, that priming does not exist per se but is the direct and intrinsic consequence of the loss of dopamine innervation of the striatum (and other target structures), meaning that the first injections of dopaminergic drugs only exacerbate those mechanisms (sensitization) but do not induce them. Chronicity and pulsatility of subsequent dopaminergic treatment only exacerbates the likelihood of developing dyskinesia.

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Striatal Proteomic Analysis Suggests that First L-Dopa Dose Equates to Chronic Exposure

Cited by 48 publications

References 57 publications

Differential striatal spine pathology in Parkinson’s disease and cocaine addiction: A key role of dopamine?

Differential striatal spine pathology in Parkinson’s disease and cocaine addiction: A key role of dopamine?

L-DOPA-induced dyskinesia is associated with regional increase of striatal dynorphin peptides as elucidated by imaging mass spectrometry

Priming for l-dopa-induced dyskinesia in Parkinson’s disease: A feature inherent to the treatment or the disease?

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