14 research outputs found
Effect of streptozotocin-induced diabetes on the gene expression and biological activity of 3 beta-hydroxysteroid dehydrogenase in the rat spinal cord
Abnormal secretion of steroids by the adrenals
and gonads is one of the disturbances occurring in diabetics
but the impact of diabetes on steroid formation in the nervous
system has never been studied. However, it is well
known that numerous actions of peripheral steroids on the
nervous system require their conversion into neuroactive
metabolites within the neural tissue. As this in situ steroid
synthesis/metabolism is crucial for the control of several
neurobiological functions, we investigated the effects of
streptozotocin-induced diabetes on the gene expression and
activity of 3 -hydroxysteroid dehydrogenase in the spinal
cord, a pivotal structure involved in sensorimotor and neurovegetative
mechanisms. 3 -Hydroxysteroid dehydrogenase
is a key enzyme which participates to the biosynthesis
of all classes of steroids by converting 5-3 -hydroxysteroids
such as pregnenolone and dehydroepiandrosterone
into 4-3-ketosteroids as progesterone and androstenedione,
respectively. Reverse transcription coupled with quantitative
real-time polymerase chain reaction revealed that 3 -hydroxysteroid
dehydrogenase gene was over-expressed in the spinal
cord of streptozotocin-treated rats compared with controls.
Pulse-chase experiments combined with high performance
liquid chromatography and continuous flow detection
of newly-synthesized steroids showed an increase of 3 -
hydroxysteroid dehydrogenase activity responsible for a hyper-
production of progesterone in the spinal cord of diabetic
rats. This up-regulation of progesterone biosynthesis was
concomitant with a decrease of its transformation into tetrahydroprogesterone,
a process which facilitated progesterone
accumulation in the spinal cord of streptozotocin-treated
rats. Since progesterone is a potent neuroprotective steroid,
increase of its production appeared as an endogenous molecular
and biochemical mechanism triggered by spinal nerve
cells to cope with degenerative effects of streptozotocininduced
diabetes. Our results constitute the first direct evidence
showing an impact of diabetes on steroid biosynthetic
and metabolic pathways in the nervous system. The data
open new perspectives for the modulation of deleterious
effects of diabetes by neuroprotective steroids
Neuroactive steroids : state of the art and new perspectives
Neuroactive steroids include synthetic steroidal
compounds and endogenous steroids, produced
by endocrine glands (hormonal steroids) or the
nervous tissue (neurosteroids), which regulate neural
functions. These steroids bind to nuclear receptors or
act through the activation of membrane-associated
signaling pathways to modulate various important
processes including the development of the nervous system, neural plasticity and the adaptive responses of
neurons and glial cells under pathological conditions.
Reviewed and updated in the present paper are the
pleiotropic and protective abilities of neuroactive
steroids. The fundamental evidence and knowledge
gained constitute a profound background that offers
interesting possibilities for developing effective strategies
against several disorders of the nervous system
Assessment of neuroactive steroid formation in diabetic rat spinal cord using high-performance liquid chromatography and continuous flow scintillation detection
The combination of pulse-chase experiments with high-performance liquid chromatography and continuous flow scintillation detection was
used successfully to determine the effects of chronic diabetes on neurosteroid production in the adult rat spinal cord. The long-term diabetes was
induced by treatment of adult rats with streptozotocin. In the first part, the review provides an extensive description of the HPLC combined with
continuous flow scintillation detection method, its advantages and appropriateness for the question investigated. Afterwards, the paper shows that
progesterone formation is up-regulated in the spinal cord of diabetic rats while the biosynthesis of tetrahydroprogesterone decreased. The downregulation
of tetrahydroprogesterone appeared as a mechanism facilitating progesterone accumulation in the spinal cord of streptozotocin-treated
rats. Progesterone is well known to be a potent neuroprotective steroid. Enhancement of its biosynthesis may be an endogenous mechanism
triggered by neural cells in the spinal tissue to cope with degenerative effects provoked by chronic diabetes. Since steroid metabolism in the spinal
cord is pivotal for the modulation of several neurobiological processes including sensorimotor activities, the data analyzed herein may constitute
useful information for the development of efficient strategies against deleterious effects of diabetes on the nervous system
HS3ST2 expression is critical for the abnormal phosphorylation of tau in Alzheimer's disease-related tau pathology
Item does not contain fulltextHeparan sulphate (glucosamine) 3-O-sulphotransferase 2 (HS3ST2, also known as 3OST2) is an enzyme predominantly expressed in neurons wherein it generates rare 3-O-sulphated domains of unknown functions in heparan sulphates. In Alzheimer's disease, heparan sulphates accumulate at the intracellular level in disease neurons where they co-localize with the neurofibrillary pathology, while they persist at the neuronal cell membrane in normal brain. However, it is unknown whether HS3ST2 and its 3-O-sulphated heparan sulphate products are involved in the mechanisms leading to the abnormal phosphorylation of tau in Alzheimer's disease and related tauopathies. Here, we first measured the transcript levels of all human heparan sulphate sulphotransferases in hippocampus of Alzheimer's disease (n = 8; 76.8 +/- 3.5 years old) and found increased expression of HS3ST2 (P < 0.001) compared with control brain (n = 8; 67.8 +/- 2.9 years old). Then, to investigate whether the membrane-associated 3-O-sulphated heparan sulphates translocate to the intracellular level under pathological conditions, we used two cell models of tauopathy in neuro-differentiated SH-SY5Y cells: a tau mutation-dependent model in cells expressing human tau carrying the P301L mutation hTau(P301L), and a tau mutation-independent model in where tau hyperphosphorylation is induced by oxidative stress. Confocal microscopy, fluorescence resonance energy transfer, and western blot analyses showed that 3-O-sulphated heparan sulphates can be internalized into cells where they interact with tau, promoting its abnormal phosphorylation, but not that of p38 or NF-kappaB p65. We showed, in vitro, that the 3-O-sulphated heparan sulphates bind to tau, but not to GSK3B, protein kinase A or protein phosphatase 2, inducing its abnormal phosphorylation. Finally, we demonstrated in a zebrafish model of tauopathy expressing the hTau(P301L), that inhibiting hs3st2 (also known as 3ost2) expression results in a strong inhibition of the abnormally phosphorylated tau epitopes in brain and in spinal cord, leading to a complete recovery of motor neuronal axons length (n = 25; P < 0.005) and of the animal motor response to touching stimuli (n = 150; P < 0.005). Our findings indicate that HS3ST2 centrally participates to the molecular mechanisms leading the abnormal phosphorylation of tau. By interacting with tau at the intracellular level, the 3-O-sulphated heparan sulphates produced by HS3ST2 might act as molecular chaperones allowing the abnormal phosphorylation of tau. We propose HS3ST2 as a novel therapeutic target for Alzheimer's disease