Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease

Lipoxygenase (LOX) activity has been implicated in neurodegenerative disorders such as Alzheimer&#39;s disease, but its effects in Parkinson&#39;s disease ...

SRI International

Systemic administration of ubiquitin-proteasome system inhibitors to rodents has been reported to induce certain behavioral and neuropathological features of Parkinson's disease. The goal of this study was to replicate these observations by administering a proteasome inhibitor (PSI) to rats using McNaught and colleagues' protocol. No alterations in locomotor activity or striatal dopamine and its metabolites were observed. Differences in nigral dopaminergic cell number between proteasome inhibitor- and vehicle-treated rats and inclusion bodies were not found. Extending the time of survival after administration and using different solvents failed to alter results, indicating this proteasome inhibitor does not consistently produce the selective toxicity and pathological hallmarks characterizing Parkinson's disease.

Lack of nigrostriatal pathology in a rat model of proteasome inhibition.

Mutations in the gene for DJ-1 have been associated with early-onset autosomal recessive parkinsonism. Previous studies of null DJ-1 mice have shown alterations in striatal dopamine (DA) transmission with no DAergic cell loss. Here we characterize a new line of DJ-1-deficient mice. A subtle locomotor deficit was present in the absence of a change in striatal DA levels. However, increased [(3)H]-DA synaptosomal uptake and [(125)I]-RTI-121 binding were measured in null DJ-1 vs. wild-type mice. Western analyses of synaptosomes revealed significantly higher dopamine transporter (DAT) levels in pre-synaptic membrane fractions. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure exacerbated striatal DA depletion in null DJ-1 mice with no difference in DAergic nigral cell loss. Furthermore, increased 1-methyl-4-phenylpyridinium (MPP(+)) synaptosomal uptake and enhanced MPP(+) accumulation were measured in DJ-1-deficient vs. control striatum. Thus, under null DJ-1 conditions, DAT changes likely contribute to altered DA neurotransmission and enhanced sensitivity to toxins that utilize DAT for nigrostriatal entry.

Increased vulnerability of nigrostriatal terminals in DJ-1-deficient mice is mediated by the dopamine transporter.

Oxidative damage of membrane polyunsaturated fatty acids (PUFA) is thought to play a major role in mitochondrial dysfunction related to Parkinson's disease (PD). The toxic products formed by PUFA oxidation inflict further damage on cellular components and contribute to neuronal degeneration. Here, we tested the hypothesis that isotopic reinforcement, by deuteration of the bisallylic sites most susceptible to oxidation in PUFA may provide at least partial protection against nigrostriatal injury in a mouse model of oxidative stress and cell death, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Mice were fed a fat-free diet supplemented with saturated acids, oleic acid and essential PUFA: either normal, hydrogenated linoleic (LA, 18:2n-6) and α-linolenic (ALA, 18:3n-3) or deuterated 11,11-D2-LA and 11,11,14,14-D4-ALA in a ratio of 1:1 (to a total of 10% mass fat) for 6 days; each group was divided into two cohorts receiving either MPTP or saline and then continued on respective diets for 6 days. Brain homogenates from mice receiving deuterated PUFA (D-PUFA) vs. hydrogenated PUFA (H-PUFA) demonstrated a significant incorporation of deuterium as measured by isotope ratio mass-spectrometry. Following MPTP exposure, mice fed H-PUFA revealed 78.7% striatal dopamine (DA) depletion compared to a 46.8% reduction in the D-PUFA cohort (as compared to their respective saline-treated controls), indicating a significant improvement in DA concentration with D-PUFA. Similarly, higher levels of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were detected in MPTP-exposure mice administered D-PUFA; however, saline-treated mice revealed no change in DA or DOPAC levels. Western blot analyses of tyrosine hydroxylase (TH) confirmed neuroprotection with D-PUFA, as striatal homogenates showed higher levels of TH immunoreactivity in D-PUFA (88.5% control) vs. H-PUFA (50.4% control) in the MPTP-treated cohorts. In the substantia nigra, a significant improvement was noted in the number of nigral dopaminergic neurons following MPTP exposure in the D-PUFA (79.5% control) vs. H-PUFA (58.8% control) mice using unbiased stereological cell counting. Taken together, these findings indicate that dietary isotopic reinforcement with D-PUFA partially protects against nigrostriatal damage from oxidative injury elicited by MPTP in mice.

Isotopic reinforcement of essential polyunsaturated fatty acids diminishes nigrostriatal degeneration in a mouse model of Parkinson's disease.

Loss of DJ-1 function contributes to pathogenesis in Parkinson's disease. Here, we investigate the impact of aging and DJ-1 deficiency in transgenic mice. Ventral midbrain from young DJ-1-deficient mice revealed no change in 4-hydroxy-2-nonenal (4-HNE), but HSP60, HSP40 and striatal dopamine turnover were significantly elevated compared to wildtype. In aged mice, the chaperone response observed in wildtype animals was absent from DJ-1-deficient transgenics, and nigral 4-HNE immunoreactivity was enhanced. These changes were concomitant with increased striatal dopamine levels and uptake. Thus, increased oxidants and diminished protein quality control may contribute to nigral oxidative damage with aging in the model.

Evidence of oxidative stress in young and aged DJ-1-deficient mice.

Perte de fonction DJ-1 contribue &agrave; la pathogen&egrave;se de la maladie de Parkinson. Ici, nous &eacute;tudions l&#39;impact d&#39;une carence en vieillissement et DJ-1 chez les souris transg&eacute;niques. M&eacute;senc&eacute;phalique ventral de jeunes souris d&eacute;ficientes en DJ-1 a r&eacute;v&eacute;l&eacute; aucun changement dans la 4-hydroxy-2-nonenal (4-HNE), mais HSP60, HSP40 et striatale chiffre d&#39;affaires de dopamine ont &eacute;t&eacute; significativement &eacute;lev&eacute;s par rapport au type sauvage. Chez les souris &acirc;g&eacute;es, la r&eacute;ponse de chaperon observ&eacute;e chez les animaux de type sauvage a &eacute;t&eacute; absente de DJ-1-deficient transg&eacute;niques et INEF immunor&eacute;activit&eacute; HNE-4 a &eacute;t&eacute; am&eacute;lior&eacute;e. Ces changements ont &eacute;t&eacute; concomitantes avec les niveaux de dopamine striatale accrue et d&#39;absorption. Ainsi, oxydants accrues et contr&ocirc;le de qualit&eacute; de prot&eacute;ine r&eacute;duite peuvent contribuer aux dommages oxydatifs INEF au vieillissement dans le mod&egrave;le.

Preuve du stress oxydatif chez les souris d&eacute;ficientes en DJ-1 jeunes et &acirc;g&eacute;s.

Perdita di funzione di DJ-1 contribuisce alla patogenesi nel morbo di Parkinson. Qui, si indaga l&#39;impatto dell&#39;invecchiamento e DJ-1 deficit nei topi transgenici. Mesencefalo ventrale da giovani topi di DJ-1-carenti non rivelato alcun cambiamento nel 4-idrossi-2-nonenale (4-HNE), ma fatturato dopamina HSP60, HSP40 e striatal furono significativamente elevati rispetto ai wildtype. Nei topi anziani, la risposta di chaperone osservata negli animali wildtype era assente da DJ-1-carenti transgenica e nigral immunoreattivit&agrave; 4-HNE &egrave; stato migliorato. Questi cambiamenti sono stati concomitanti con maggiore striatal della dopamina livelli e assorbimento. Cos&igrave;, ossidanti aumentate e diminuita della proteina di controllo di qualit&agrave; pu&ograve; contribuire al danno ossidativo nigral con l&#39;invecchiamento del modello.

Vivian P. Chou

Center for Health Sciences

SRI International

Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease

Vivian P. Chou

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Center for Health Sciences

SRI International

Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease

Center for Health Sciences