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Progressive Demyelination (progressive + demyelination)
Selected AbstractsDelay of myelin formation in arylsulphatase A-deficient miceEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2005Afshin Yaghootfam Abstract Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulphatase A (ASA). This leads to the accumulation of the sphingolipid 3-O-sulphogalactosylceramide (sulphatide) and progressive demyelination in the nervous system of MLD patients. The mechanisms and development of pathology in the disease are still largely unknown. In this study we investigate how the inability to degrade sulphatide affects the formation of myelin in ASA-deficient (ASA,/,) mice. In mice at 2 weeks of age there was a substantial reduction in myelin basic protein (MBP) mRNA and protein. This was confirmed by an immunohistochemical analysis. MBP mRNA and protein, however, reach normal levels at 3 weeks of age. Proteolipid protein (PLP) and MAL mRNA were also reduced in ASA,/, mice at 2 weeks of age; whereas the level of PLP mRNA was normal at 26 weeks of age, MAL mRNA expression remained reduced up to this age. In situ hybridization revealed no significant changes in the number of myelinating oligodendrocytes or oligodendrocyte precursor cells in ASA,/, mice. These results suggest that oligodendrocyte differentiation was normal in ASA,/, mice. No differences were found in the expression of the sulphatide synthesizing enzymes cerebroside sulphotransferase and UDP-galactose : ceramide galactosyltransferase. Our data demonstrate a delay in myelin formation in ASA,/, mice. This raises the possibility that similar alterations in MLD patients may contribute to the pathology of the disease. [source] Oligodendrocyte-specific ceramide galactosyltransferase (CGT) expression phenotypically rescues CGT-deficient mice and demonstrates that CGT activity does not limit brain galactosylceramide levelGLIA, Issue 3 2005Inge Zöller Abstract Galactosylceramide (GalC) is the major sphingolipid of the myelin membrane. Mice lacking GalC due to ceramide galactosyltransferase (CGT) deficiency form unstable and functionally affected myelin and exhibit a progressive demyelination, accompanied by severe motor coordination deficits. In addition to oligodendrocytes, CGT is also expressed in other cells, e.g., neurons and astrocytes. We examined the possibility that lack of CGT in these cells contributes to the phenotype of CGT-deficient mice. Toward this aim, we generated transgenic mice expressing CGT under the control of oligodendrocyte-specific proteolipid protein (PLP) promoter and examined the possibility of a transgenic rescue of CGT-deficient mice. CGT-deficient mice expressing the PLP-CGT transgene did not show any behavioral abnormalities, normal myelin structure, and MBP levels. CGT activity as well as GalC and sulfatide levels of rescued mice were not significantly different from wild-type controls. Thus, transgenic rescue with the PLP-CGT transgene was apparently complete. In contrast to wild-type and rescued mice, PLP-CGT transgenic mice on a wild-type background exhibited significantly elevated CGT activity which directly correlated with an increase in non-hydroxy fatty acid (NFA)-GalC, but not ,-hydroxy fatty acid (HFA)-GalC. HFA-GalC decreased in adult transgenic mice, indicating that NFA-GalC, but not HFA-GalC levels are limited by CGT activity. As a consequence, the total amount of GalC is unchanged over a rather wide range of CGT expression levels in the mouse brain. Our results indicate that loss of CGT in oligodendrocytes is exclusively responsible for the myelin structural deficits, demyelination, and behavioral abnormalities in CGT-deficient mice. © 2005 Wiley-Liss, Inc. [source] Lorenzo's oil, adrenoleukodystrophy, and the blood, brain barrierJOURNAL OF NEUROCHEMISTRY, Issue 2002E. J. Murphy Adrenoleukodystrophy is a rapid, progressive demyelinating disease affecting the CNS that is characterized by large increases in plasma and tissue very long saturated fatty acids (VLCFA). Lorenzo's oil (LO), consisting of erucic (22:1 n-9) and oleic (18:1 n-9) acid in a triglyceride form, is a dietary therapy effective in reducing plasma and tissue VLCFA. Despite the decreased VLCFA, clinical studies indicated that LO failed to stop the progressive demyelination, suggesting that erucic acid, the active component of LO, did not cross the BBB. We addressed this question by infusing [14-14C] 22:1 n-9 (170 ,Ci/kg) into male rats using two different infusion paradigms. The radiotracer was infused (i.v.) into awake, adult male rats over a 10-min period or infused (i.c.v.) into the fourth ventricle over a 7-day period using an osmotic mini-pump. Brains were removed from the cranium, frozen in liquid nitrogen, lipids extracted, and separated using standard techniques. [1-14C] 20:4 n-6 was infused (i.v.) and used as a positive control. Following i.v. infusion, 0.011% of the erucic acid was extracted by the brain, compared to 0.055% of the arachidonic acid. About 60% of the brain erucic acid was found in the aqueous fraction compared to 30% for arachidonic acid. Further, erucic acid was targeted to cholesteryl ester and triacylglyceride pools, whereas arachidonic acid was targeted to phospholipid pools. In animals infused i.c.v., 0.078% of the dose was taken up and about 60% of the erucic acid was targeted to phospholipid pools. These results clearly demonstrate that erucic acid crosses the BBB, similar to arachidonic acid, and is incorporated into specific lipid pools. Acknowledgements:, This work was supported by The Myelin Project. [source] Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 79JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2003U Del Carro Peripheral neuropathy is one of the most common secondary complications of diabetes mellitus, causing severe and prolonged morbidity. However, clinical and experimental studies have reported that careful glucose control may prevent, stabilize, and/or reverse neuropathy and other chronic diabetic complications. Unfortunately, insulin therapy does not prevent the development or progression of chronic lesions in the vessels, kidneys, eyes, or nerves of the diabetic patient. There is great interest in investigating other forms of endocrine replacement therapy, such as transplantation of the pancreas or of the islets of Langerhans (IT). Diabetic polyneuropathy (DP) evolution is characterized by progressive demyelination and axonal loss and is manifested by signs and symptoms on physical examination and abnormalities in nerve conduction studies (NCS). NCS provide reliable, noninvasive, objective measures of peripheral nerve function and constitute the most important technique for the evaluation of the severity of DP in clinical trials. Several research groups have demonstrated that skin biopsy with measurement of intraepidermal nerve fiber density is another method minimally invasive and repeatable that provides direct pathologic evidence of axonal damage in diabetic neuropathy. Fifty-one consecutive IDDM patients with or without end stage renal disease were enrolled at the moment of islet (Is), kidney (KD), kidney-pancreas (KP) or kidney-islet (KI) transplantation. Patients underwent skin biopsy punch, neurologic examination and neurophysiological investigation. Particularly, 20 pts underwent KP tx, 16 KD tx, 10 islet tx and 5 KI. The patients were comparable for duration of diabetes, dialysis (when present), age, lipid profile. In half of the patients a follow-up of 2 years has been reached. After KP tx, and partially with KI, a complete normalization of glycometabolic control has been achieved, with statistically lower HbA1c in comparison with KD group (KP = 6.2; 0.1% vs. KD = 8.4; 0.5%; p < 0.01). In the KI/Is group, a long-term restoration of islet endocrine function has been achieved, with insulin independence. When this has been lost, a persistent secretion of C-peptide was shown for a long period of time. This was correlated with a global improvement quality of life and vascular structure. Preliminary results will be presented. [source] Insulin-like growth factor-1 and neurotrophin-3 gene therapy prevents motor decline in an X-linked adrenoleukodystrophy mouse model,ANNALS OF NEUROLOGY, Issue 1 2009Roberto Mastroeni MSc X-linked adrenoleukodystrophy (X-ALD) is the most common inherited peroxisomal disorder characterized by a progressive demyelination of the central nervous system. The marked loss of myelin and oligodendrocytes observed in the disease prompted us to evaluate the therapeutic potential of insulin-like growth factor-1 and neurotrophin-3, two potent inducers of myelin formation and oligodendrocyte survival. Viral vectors engineered to produce insulin-like growth factor-1 or neurotrophin-3 were administrated into the cerebrospinal fluid of an X-linked adrenoleukodystrophy mouse model. We show that viral-based, long-lasting delivery of insulin-like growth factor-1 and neurotrophin-3 significantly halts the progression of the disease and leads to potent protective effect against the demyelination process. Ann Neurol 2009;66:117,122 [source] | |||||||||||||