Vol 1-9 Mini Review

Arachidonic acid in Alzheimer's disease

Mélanie H. Thomas1, Sandra Pelleieux1,2, Nicolas Vitale3, Jean Luc Olivier1,2

1Unité de Recherche Aliment et Fonctionnalité des Produits Animaux (URAFPA), INRA USC 0340, Université de Lorraine, Nancy, France
2Service de Biochimie-Biologie Moléculaire, Hôpital Central, CHU de Nancy, Nancy, France
3Institut des Neurosciences Cellulaires et Intégratives (INCI), UPR CNRS 3212, Université de Strasbourg, Strasbourg, France

Alzheimer’s disease is a very complex disease in which neuroinflammation and synaptic dysfunctions play a critical role in association with the two well-known molecular agents of the disease, the Aβ1-42 peptide oligomers and the hyperphosphorylated tau protein. Arachidonic acid, the main member of the ω-6 series, is quantitatively the second polyunsaturated fatty acid in brain and is mainly esterified in membrane phospholipids. It is specifically released by the cytosolic phospholipase A2 whose inhibition or gene suppression counteract the deleterious effects of Aβ1-42 peptide oligomers on cognitive abilities. Arachidonic acid can be reincorporated under the action of the acyl-CoA synthetase 4 and lysophospholipid acyltransferases which remain to be characterized. Free arachidonic acid can be involved in Alzheimer’s disease through several mechanisms. First it is converted by cyclooxygenases-1/2 and the specific prostaglandin synthases into PGE2 and PGD2 which contributes to the occurrence and progression of neuroinflammation. Neuroinflammation has positive as well as negative effects, by favoring Aβ1-42 peptide clearance on one hand and by increasing the production of neurotoxic compounds on the other hand. Second, free arachidonic acid is also involved in synaptic functions as a retrograde messenger and as a regulator of neuromediator exocytosis. Third, some studies indicated that free arachidonic acid and its derivatives activate kinases involved in tau hyperphosphorylation. In addition, the dietary intakes of arachidonic acid in western food increased in the last period. Taken together, these various reports support the hypothesis that arachidonic acid is interesting target in nutrition-based preventive strategies against this disease.

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Vol 1-9 Mini Review

When transporters fail to be transported:how to rescue folding-deficient SLC6 transporters

Sonja Sucic, Ameya Kasture, H. M. Mazhar Asjad, Carina Kern, Ali El-Kasaby and Michael Freissmuth*

Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria

 The human dopamine transporter (hDAT) belongs to the solute carrier 6 (SLC6) gene family. Point mutations in hDAT (SLC6A3) have been linked to a syndrome of dopamine transporter deficiency or infantile dystonia/parkinsonism. The mutations impair DAT folding, causing retention of variant DATs in the endoplasmic reticulum and subsequently impair transport activity. The folding trajectory of DAT itself is not understood, though many insights have been gained from studies of folding-deficient mutants of the closely related serotonin transporter (SERT); i.e. their functional rescue by pharmacochaperoning with (nor)ibogaine or heat-shock protein inhibitors. We recently provided a proof-of-principle that folding-deficits in DAT are amenable to rescue in vitro and in vivo. As a model we used the Drosophila melanogaster DAT mutant dDAT-G108Q, which phenocopies the fumin/sleepless DAT-knockout. Treatment with noribogaine and/or HSP70 inhibitor pifithrin-μ restored folding of, and dopamine transport by, dDAT-G108Q, its axonal delivery and normal sleep time in mutant flies. The possibility of functional rescue of misfolded DATs in living flies by pharmacochaperoning grants new therapeutic prospects in the remedy of folding diseases, not only in hDAT, but also in other SLC6 transporters, in particular mutants of the creatine transporter-1, which give rise to X-linked mental retardation.

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Vol 1-9 Mini Review

Excitatory/inhibitory balance of serotonergic axon connectivity in the brain

Arnauld Belmer1, Vanessa Lanoue3, Omkar L. Patkar1, and Selena E. Bartlett1,2

1Translational Research Institute, Queensland University of Technology (QUT), Brisbane, Australia
2Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology (QUT), Brisbane, Australia
3Queensland Brain Institute (QBI), The University of Queensland, Brisbane, Australia

 Serotonin neurons originate from the brainstem raphe nuclei and innervate the entire brain to regulate mood, emotion, sleep, appetite and aggression. Previous electron microscopy (EM) studies have revealed that 5-HT boutons directly contact several neuronal populations via asymmetrical (excitatory) or symmetrical (inhibitory) synapses. Additionally, 5-HT boutons sometimes form “triads” with the pre and postsynaptic components of asymmetrical or symmetrical synapses to modulate their activity. However, the exact proportion and distribution of 5-HT excitatory/inhibitory synapses and triads within the entire brain remains poorly described. Recently, we have published a novel semi-quantitative approach which combines fluorescent confocal microscopy and 3D reconstruction of 5-HT fibers apposed to excitatory and inhibitory neurochemical synapses (triads). Here, we review the similarities and differences in the distribution of 5-HT asymmetrical/symmetrical synapses observed in EM and the distribution of 5-HT excitatory/inhibitory triads quantified in our recent study. We further put into perspective the possible physiological role played by 5-HT triads in the regulation of glutamate and GABA signaling in these various brain regions.

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Vol 1-9 Mini Review

SLC41A1 and TRPM7 in magnesium homeostasis and genetic risk for Parkinson’s disease

Morgan Sturgeon1, Perry Wu2, and Robert Cornell1,2

1Molecular and Cell Biology Graduate Program, University of Iowa, Iowa City, Iowa
2Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa

 Parkinson’s disease (PD) is a neurodegenerative disorder of the central nervous system with a clinically heterogeneous presentation that includes progressive loss of dopaminergic (DA) neurons in the substantia nigra. A minority of PD cases are familial and are caused by mutations in single genes. Most cases, however, are idiopathic PD, a complex multifactorial disorder with environmental and genetic contributors to etiology. Here, we first briefly summarize published evidence that among environmental contributors is dietary deficiency of magnesium. We then review genetic data suggesting that mutations in genes encoding two proteins contributing to cellular magnesium homeostasis confer risk for PD or other Parkinsonian conditions. First, the gene encoding magnesium transporter SLC41A1 is, among others, a candidate for the causative gene in the PARK16 locus where variation is associated with risk for idiopathic Parkinsonian disease. Studies of the function of SLC41A1 in animal models are needed to test whether this protein has a role in maintenance of dopaminergic neurons. Second, in a small study, a hypomorphic variant of TRPM7, a magnesium-permeable channel, was over-represented in cases of amyotrophic lateral sclerosis/ Parkinson dementia complex versus controls from the same ethnic group. Although this association was not detected in a second study, in zebrafish Trpm7 is necessary for terminal differentiation and reduction of toxin-sensitivity in dopaminergic neurons. Overall, epidemiological results support the possibility that mutations in genes relevant to magnesium homeostasis would alter PD risk, but deeper genetic analyses of PD patients are necessary to confirm whether SLC41A1 and TRPM7 are among such genes.

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Vol 1-9 Research Article

Parkinsonism in both members of married couples

A.H. Rajput, MBBS, FRCPC; A. Rajput, MD, FRCPC

Saskatchewan Movement Disorders Program, University of Saskatchewan/ Saskatoon Health Region

Parkinsonism in both spouses has been reported in only 20 couples in the literature so far. Six of the studies included only one or two couples, but one study reported nine couples. Fifteen of the couples reported by others consisted of only clinical data. By contrast, our study of five couples had detailed clinical, pathological and genetic observation on all ten individuals. We found no evidence of person-to-person transmission of parkinsonism. Details of that study are provided in this review.

The literature evidence to date indicates that neither Parkinson’s disease nor other common parkinson variants – multiple system atrophy or progressive supranuclear palsy are transmitted by sexual or close personal contact in the married couples. As well, these syndromes are not based on shared environments or same genetic mutation.

The best explanation for parkinsonism in both partners of non-consanguineous couples is, that Parkinson syndrome in each spouse is a coincidental disorder

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