4-hydroxy-2-nonenal and Neuronal-Ceroid-Lipofuscinoses

The juvenile form of neuronal ceroid lipofuscinosis (JNCL) is caused by mutations in the CLN3 gene, and is characterized by progressive loss of vision and development of motor deficits. A few patients exhibit a more protracted clinical course and are diagnosed with protracted JNCL (PJNCL). Here, we report the autopsy in a case of PJNCL in a 55-year-old male and immunohistochemical examination of the involvement of oxidative stress and glutamate excitotoxicity in neurodegeneration. The patient was born to consanguineous parents (I assume this means that the parents were related. If not, then the sentence will need to be changed again.) and had brothers with similar neurological disease. He showed mental retardation and visual impairment in the first decade which gradually developed along with motor dysfunction for over 40 years. At autopsy, the cerebral pyramidal neurons revealed deposition of lipopigments, which demonstrated 'finger print' and curvilinear profiles on electron microscopy. He also exhibited cerebellar cortical atrophy, fibrillary gliosis in the white matter, and rarefication in the globus pallidus. Immunohistochemically, the number of neurons immunoreactive for advanced glycation end product was elevated in the cerebellar cortex and midbrain. Immunoreactivity for excitatory amino acid transporter 1 was reduced in the cerebellar dentate and inferior olivary nuclei. These findings suggest that oxidative damage to proteins and disturbed glutamate transport can be involved in PJNCL.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Autopsy; Brain; Deoxyguanosine; Family Health; Glycation End Products, Advanced; Humans; Immunohistochemistry; Male; Middle Aged; Neuronal Ceroid-Lipofuscinoses; Neurons

Retinal degeneration is an early and progressive event in many forms of neuronal ceroid lipofuscinoses (NCLs), a heterogeneous group of neurodegenerative disorders with unknown pathogenesis. We here used the mutant motor neuron degeneration (mnd) mouse, a late-infantile NCL variant, to investigate the retinal oxidative state and apoptotic cell death as a function of age and sex. Total superoxide dismutase (SOD) activities and thiobarbituric acid-reactive substance (TBARS) levels revealed progressive increases in retinal oxyradicals and lipid peroxides of mnd mice of both sexes. Female mnd retinas showed a higher oxidation rate and consistently exhibited the 4-hydroxy-2-nonenal (4-HNE)-adducts staining and advanced histopathologic profile when compared to male mnd retinas matched for age. In situ DNA fragmentation (TUNEL staining) appeared in the outer nuclear layer (ONL) as early as 1 month of age. At 4 months, there were more intense and numerous TUNEL-positive cells in the same layer and in the inner nuclear (INL) and ganglion cell (GCL) layers; whereas at 8 months TUNEL staining was restricted to a few scattered cells in the INL and GCL, when a severe retinal cell loss had occurred. Caspase-3 activation confirmed apoptotic demise and its processing turned out to be higher in mnd females than males. These results demonstrate the involvement of oxidation and apoptotic processes in mnd mouse retinopathy and highlight sex-related differences in retinal vulnerability to oxidative stress and damage.

Topics: Aldehydes; Animals; Apoptosis; Caspase 3; Caspases; Disease Models, Animal; Enzyme Activation; Female; Immunohistochemistry; In Situ Nick-End Labeling; Male; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Neuronal Ceroid-Lipofuscinoses; Oxidation-Reduction; Oxidative Stress; Retina; Retinal Degeneration; Sex Factors; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Canine ceroid-lipofuscinosis (CCL) is a model of the juvenile type of Batten disease in human patients. Abnormalities have been reported previously in 4-hydroxynonenal (HNE) levels in English setters with CCL. The purpose of this study was to examine the sources of HNE in neutrophil membranes and plasma of CCL dogs. The fatty acid composition of neutrophil phospholipids, i.e., phosphatidyl ethanolamine and phosphatidyl serine, was determined by gas-liquid-chromatography (GLC) since some polyunsaturated fatty acids (PUFA) are precursors of HNE. The copper catalyzed peroxidation of low density lipoprotein (LDL) was examined to determine the susceptibility of LDL from CCL dogs to peroxidation. The results indicated that a number of PUFA precursors of HNE decreased in affected an carrier neutrophil phospholipids, indicating that this source of HNE may be disease specific. The Cu++ catalyzed formation of HNE from LDL demonstrated that carrier and normal LDL produced large amounts of HNE, while LDL from affected dogs required much higher concentrations of Cu++ for maximal HNE production. These results provide additional support for the role of HNE in the pathogenetic events in NCL and support the view that lipid peroxidation may be an important contributor to the complex pathogenesis of the NCL.

Topics: Aldehydes; Animals; Dog Diseases; Dogs; Fatty Acids; Genetic Carrier Screening; Humans; Lipoproteins, LDL; Neuronal Ceroid-Lipofuscinoses; Neutrophils; Phosphatidylethanolamines; Phosphatidylserines; Reference Values

Topics: Aldehydes; Animals; Calcimycin; Cell Line, Transformed; Dogs; Herpesvirus 4, Human; Humans; Lymphocytes; Neuronal Ceroid-Lipofuscinoses; Neutrophils; Tetradecanoylphorbol Acetate

Previous attempts to demonstrate abnormalities in lipid peroxidation in various forms of the neuronal ceroid-lipofuscinoses (NCL) have been unrewarding up to and including the peroxide level (peroxidase). In this experiment a survey was made in a canine model of NCL to study the relative concentration of 4-hydroxynonenal (HNE), a fragment derived from an acute oxidation product of unsaturated fatty acids. Peripheral blood cells and various tissues from an affected and a normal control dog were surveyed. HNE was assayed after reacting with O-(2,3,4,5,6-pentafluorobenzyl) hydroxylamine to form the 4-hydroxynonenal (O-pentafluorobenzyl) oxime. This reaction product was then separated by capillary gas liquid chromatography (g/c) and quantitated by flame ionization. The survey showed that neutrophils isolated from affected dogs and carriers contained abnormal amounts of HNE when compared with normal control animals. Two carriers had mean values of +3,289% above normal, and neutrophils from two affected animals were +4,873% above normal. In addition, an examination of the relative HNE levels in brain, retina, retinal pigment epithelium (RPE), and kidney of an affected dog compared with a control animal also showed abnormal levels of HNE, particularly in brain (+168%) and in the RPE (+135%), the two organs exhibiting the most severe pathologic damage unique to these disorders. These findings, although preliminary, clearly document a role for HNE in this canine form of human NCLs. The well-known cytotoxic properties of HNE and other alpha,beta unsaturated aldehydes suggest a primary role in the pathogenetic events of this disorder.

Topics: Aldehydes; Animals; Biomarkers; Cell Separation; Disease Models, Animal; Dogs; Erythrocytes; Kidney; Leukocytes; Neuronal Ceroid-Lipofuscinoses; Pigment Epithelium of Eye; Retina