Aldehyde dehydrogenase (ALDH) in Alzheimer’s and Parkinson’s disease

Grünblatt, Edna; Riederer, Peter

doi:10.1007/s00702-014-1320-1

Cited by 69 publications

(50 citation statements)

References 56 publications

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“…RA is the locally synthesized, tightly regulated, active metabolite of vitamin A, which may be considered as one of the most potent endogenous small molecules in the central nervous system (CNS), controlling important neurobiological processes throughout life. RA is locally synthesized through retinol dehydrogenases (ROLDHs) and aldehyde dehydrogenases (ALDHs), and strong evidence suggests variation at the genetic and protein expression level to be implicated in the pathogenesis of neurodegenerative disorders (Grunblatt and Riederer 2014). Acting via nuclear receptor-mediated (RAR-a,b,c and RXR-a,b,c) transcriptional regulation of neuroprotective and pro-differentiative genes, a specific involvement of RA signaling in key homeostatic-and depression-related-processes has been shown.…”

Section: Introductionmentioning

confidence: 99%

Direct inhibition of retinoic acid catabolism by fluoxetine

et al. 2015

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Recent evidence from animal and human studies suggests neuroprotective effects of the SSRI fluoxetine, e.g., in the aftermath of stroke. The underlying molecular mechanisms remain to be fully defined. Because of its effects on the cytochrome P450 system (CYP450), we hypothesized that neuroprotection by fluoxetine is related to altered metabolism of retinoic acid (RA), whose CYP450-mediated degradation in brain tissue constitutes an important step in the regulation of its site-specific auto- and paracrine actions. Using traditional pharmacological in vitro assays, the effects of fluoxetine on RA degradation were probed in crude synaptosomes from rat brain and human-derived SH-SY5Y cells, and in cultures of neuron-like SH-SY5Y cells. Furthermore, retinoid-dependent effects of fluoxetine on neuronal survival following glutamate exposure were investigated in rat primary neurons cells using specific retinoid receptor antagonists. Experiments revealed dose-dependent inhibition of synaptosomal RA degradation by fluoxetine along with dose-dependent increases in RA levels in cell cultures. Furthermore, fluoxetine's neuroprotective effects against glutamate excitotoxicity in rat primary neurons were demonstrated to partially depend on RA signaling. Taken together, these findings demonstrate for the first time that the potent, pleiotropic antidepressant fluoxetine directly interacts with RA homeostasis in brain tissue, thereby exerting its neuroprotective effects.

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Section: Introductionmentioning

confidence: 99%

Direct inhibition of retinoic acid catabolism by fluoxetine

et al. 2015

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“…Accumulating evidence supports the view that in synucleinopathies putamen dopamine depletion reflects not only denervation but also a variety of functional abnormalities in the residual terminals. These abnormalities include decreased activity of aldehyde dehydrogenase (ALDH) [10,11] or L-aromatic-amino-acid decarboxylase [12,13], decreased vesicular storage of cytoplasmic dopamine [14–16], and oxidative stress related to dopamine-based free radicals [17]. …”

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confidence: 99%

Elevated cerebrospinal fluid ratios of cysteinyl-dopamine/3,4-dihydroxyphenylacetic acid in parkinsonian synucleinopathies

Goldstein

Holmes

Sullivan

et al. 2016

Parkinsonism & Related Disorders

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Introduction There is intense interest in identifying cerebrospinal fluid (CSF) biomarkers of Parkinson's disease (PD), both for early diagnosis and to track effects of putative treatments. Nigrostriatal dopamine depletion characterizes PD. Predictably, CSF levels of 3,4-dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, are decreased in PD, even in patients with recent onset of the movement disorder. Whether low CSF DOPAC is associated specifically with parkinsonism has been unclear. In the neuronal cytoplasm dopamine undergoes not only enzymatic oxidation to form DOPAC but also spontaneous oxidation to form 5-S-cysteinyl-dopamine (Cys-DA). Theoretically, oxidative stress or decreased activity of aldehyde dehydrogenase (ALDH) in the residual nigrostriatal dopaminergic neurons would increase CSF Cys-DA levels with respect to DOPAC levels. PD, parkinsonian multiple system atrophy (MSA-P), and pure autonomic failure (PAF) are synucleinopathies; however, PAF does not entail parkinsonism. We examined whether an elevated Cys-DA/DOPAC ratio provides a specific biomarker of parkinsonism in synucleinopathy patients. Methods CSF catechols were assayed in PD (n = 24), MSA-P (n = 32), PAF (n = 18), and control subjects (n = 32). Results Compared to controls, CSF DOPAC was decreased in PD and MSA-P (p < 0.0001 each). In both diseases Cys-DA/DOPAC ratios averaged more than twice control (0.14 ± 0.02 and 0.13 ± 0.02 vs. 0.05 ± 0.01, p < 0.0001 each), whereas in PAF the mean Cys-DA/DOPAC ratio was normal (0.05 ± 0.01). Conclusions CSF Cys-DA/DOPAC ratios are substantially increased in PD and MSA-P and are normal in PAF. Thus, in synucleinopathies an elevated CSF Cys-DA/DOPAC ratio seems to provide a specific biomarker of parkinsonism.

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“…), confirming the role of this gene in alcohol metabolism. ALDH1A1 , the protein product that also catalyzes conversion of retinaldehyde to retinoic acid, is involved in different molecular processes, such as regulation of marrow adiposity, anti‐oxidant defense, carcinogenesis and neurodegeneration (Grunblatt & Riederer ; Li et al . ; Nallamshetty et al .…”

Section: Discussionmentioning

confidence: 99%

Genome‐wide association study of body mass index in subjects with alcohol dependence

et al. 2015

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Outcomes related to disordered metabolism are common in alcohol dependence (AD). To investigate alterations in the regulation of body mass that occur in the context of AD, we performed a GWAS of BMI in African-Americans (AAs) and European-Americans (EAs) with AD. Subjects were recruited for genetic studies of alcohol or drug dependence, and evaluated using the Semi-Structured Assessment for Drug Dependence and Alcoholism. We investigated a total of 2,587 AAs and 2,959 EAs with DSM-IV AD diagnosis. In the stage-1 sample (N=4,137), we observed three genome-wide significant (GWS) SNP associations, rs200889048 (p=8.98*10−12) and rs12490016 (p=1.44*10−8) in EAs, and rs1630623 (p=5.14*10−9) in AAs and EAs meta-analyzed. In the stage-2 sample (N=1,409), we replicated 278, 253, and 168 of the stage-1 suggestive loci (p<5*10−4) in AAs, EAs, and AAs and EAs meta-analyzed, respectively. A meta-analysis of stage-1 and stage-2 samples (N=5,546) identified two additional GWS signals: rs28562191 in EAs (p=4.46*10−8) and rs56950471 in AAs (p=1.57*10−9). Three of the GWS loci identified (rs200889048, rs12490016, rs1630623) were not previously reported by GWAS of BMI in the general population and two of them raise interesting hypotheses: rs12490016 – a regulatory variant located within LINC00880, where there are other GWAS-identified variants associated with birth size, adiposity in newborns, and bulimia symptoms which also interact with social stress in relation to birth size; rs1630623 – a regulatory variant related to ALDH1A1, a gene involved in alcohol metabolism and adipocyte plasticity. These loci offer molecular insights regarding the regulatory mechanisms of body mass in the context of AD.

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Aldehyde dehydrogenase (ALDH) in Alzheimer’s and Parkinson’s disease

Cited by 69 publications

References 56 publications

Direct inhibition of retinoic acid catabolism by fluoxetine

Direct inhibition of retinoic acid catabolism by fluoxetine

Elevated cerebrospinal fluid ratios of cysteinyl-dopamine/3,4-dihydroxyphenylacetic acid in parkinsonian synucleinopathies

Genome‐wide association study of body mass index in subjects with alcohol dependence

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