Pathogenesis Of Human Neurodegenerative Disorders Research Articles

The Role of Cathepsin D in the Pathogenesis of Human Neurodegenerative Disorders.

In familial neurodegenerative disorders, protein aggregates form continuously because of genetic mutations that drive the synthesis of truncated or unfolded proteins. The oxidative stress imposed by neurotransmitters and environmental neurotoxins constitutes an additional threat to the folding of the proteins and the integrity of organelle membranes in neurons. Failure in degrading such altered materials compromises the function of neurons and eventually leads to neurodegeneration. The lysosomal proteolytic enzyme Cathepsin D is the only aspartic-type protease ubiquitously expressed in all the cells of the human body, and it is expressed at high level in the brain. In general, cathepsin D mediated proteolysis is essential to neuronal cell homeostasis through the degradation of unfolded or oxidized protein aggregates delivered to lysosomes via autophagy or endocytosis. More specifically, many altered neuronal proteins that hallmark neurodegenerative diseases (e.g., the amyloid precursor, α-synuclein, and huntingtin) are physiologic substrates of cathepsin D and would abnormally accumulate if not efficiently degraded by this enzyme. Furthermore, experimental evidence indicates that cathepsin D activity is linked to the metabolism of cholesterol and of glycosaminoglycans, which accounts for its involvement in neuronal plasticity. This review focuses on the unique role of cathepsin D mediated proteolysis in the pathogenesis of human neurodegenerative diseases.

Neurotrophic factors and their effects in the treatment of multiple sclerosis.

Neurotrophins are small molecules of polypeptides, which include nerve growth factor (NGF) family, glial cell line–derived neurotrophic factor (GDNF) family ligands, and neuropoietic cytokines. These factors have an important role in neural regeneration, remyelination, and regulating the development of the peripheral and central nervous systems (PNS and CNS, respectively) by intracellular signaling through specific receptors. It has been suggested that the pathogenesis of human neurodegenerative disorders may be due to an alteration in the neurotrophic factors and their receptors. The use of neurotrophic factors as therapeutic agents is a novel strategy for restoring and maintaining neuronal function during neurodegenerative disorders such as multiple sclerosis. Innate and adaptive immune responses contribute to pathology of neurodegenerative disorders. Furthermore, autoimmune and mesenchymal stem cells, by the release of neurotrophic factors, have the ability to protect neuronal population and can efficiently suppress the formation of new lesions. So, these cells may be an alternative source for delivering neurotrophic factors into the CNS.

A Role for Hemopexin in Oligodendrocyte Differentiation and Myelin Formation

Myelin formation and maintenance are crucial for the proper function of the CNS and are orchestrated by a plethora of factors including growth factors, extracellular matrix components, metalloproteases and protease inhibitors. Hemopexin (Hx) is a plasma protein with high heme binding affinity, which is also locally produced in the CNS by ependymal cells, neurons and glial cells. We have recently reported that oligodendrocytes (OLs) are the type of cells in the brain that are most susceptible to lack of Hx, as the number of iron-overloaded OLs increases in Hx-null brain, leading to oxidative tissue damage. In the current study, we found that the expression of the Myelin Basic Protein along with the density of myelinated fibers in the basal ganglia and in the motor and somatosensory cortex of Hx-null mice were strongly reduced starting at 2 months and progressively decreased with age. Myelin abnormalities were confirmed by electron microscopy and, at the functional level, resulted in the inability of Hx-null mice to perform efficiently on the Rotarod. It is likely that the poor myelination in the brain of Hx-null mice was a consequence of defective maturation of OLs as we demonstrated that the number of mature OLs was significantly reduced in mutant mice whereas that of precursor cells was normal. Finally, in vitro experiments showed that Hx promotes OL differentiation. Thus, Hx may be considered a novel OL differentiation factor and the modulation of its expression in CNS may be an important factor in the pathogenesis of human neurodegenerative disorders.

Valosin-containing Protein (VCP) in Novel Feedback Machinery between Abnormal Protein Accumulation and Transcriptional Suppression

Abnormal protein accumulation is often observed in human neurodegenerative disorders such as polyglutamine diseases and Parkinson disease. Genetic and biochemical analyses indicate that valosin-containing protein (VCP) is a crucial molecule in the pathogenesis of human neurodegenerative disorders. We report here that VCP was specifically modified in neuronal cells with abnormal protein accumulation; this modification caused the translocation of VCP into the nucleus. Modification-mimic forms of VCP induced transcriptional suppression with deacetylation of core histones, leading to cell atrophy and the decrease of de novo protein synthesis. Preventing VCP nuclear translocation in polyglutamine-expressing neuronal cells and Drosophila eyes mitigated neurite retraction and eye degenerations, respectively, concomitant with the recovery of core histone acetylation. This represents a novel feedback mechanism that regulates abnormal protein levels in the cytoplasm during physiological processes, as well as in pathological conditions such as abnormal protein accumulation in neurodegenerations.

Quinolinate-like neurotoxicity produced by aminooxyacetic acid in rat striatum

The endogenous tryptophan metabolite quinolinic acid elicits in rodent brain a pattern of neuronal degeneration which resembles that caused by L-glutamate. Its qualities as a neurotoxic agent raised the hypothesis that quinolinic acid might be involved in the pathogenesis of human neurodegenerative disorders. Kynurenic acid, another endogenous tryptophan metabolite and preferential N-methyl-D-aspartate (NMDA) antagonist, has been shown to block quinolinic acid neurotoxicity. Here we report that microinjections of aminooxyacetic acid (AOAA), an inhibitor of kynurenine transaminase and of other pyridoxal phosphate-dependent enzymes, into the rat striatum produce neuronal damage resembling that caused by quinolinic acid. AOAA-induced striatal lesions can be prevented by kynurenic acid and the selective NMDA antagonist 2-amino-7-phosphonoheptanoic acid. These results suggest that AOAA produces excitotoxic lesions by depleting brain concentrations of kynurenic acid (inhibition of synthetic enzyme) or due to impairment of intracellular energy metabolism (depletion of cell energy resources). The concept of deficient neuroprotection due to metabolic defects might help to clarify the pathogenesis of human neurodegenerative disorders and to develop strategies that may be useful in their treatment.

Quinolinic acid phosphoribosyltransferase: purification and partial characterization from human liver and brain.

Quinolinic acid phosphoribosyltransferase (QPRT) [EC 2.4.2.19] from human liver and brain was purified to homogeneity. Identity of the pure enzymes isolated from the two organs was proven by biochemical, physiocochemical and, following the production and partial purification of anti-liver QPRT antibodies, immunological techniques. Human QPRT has a molecular weight of 170,000 and consists of five identical subunits. Kinetic analyses revealed a Km of 5.6 microM for the substrate (quinolinic acid) and 23 microM for the co-substrate (phosphoribosylpyrophosphate). Enzyme activity was dependent on Mg2+ (optimal concentration: 1 mM) and was inhibited by the enzymatic by-product, inorganic pyrophosphate. Pure QPRT and its antibodies will constitute useful tools in the examination of the possible role of quinolinic acid in the pathogenesis of human neurodegenerative disorders.

Chronic infusion of endogenous excitatory amino acids into rat striatum and hippocampus

The effects of chronic intrastriatal and intrahippocampal infusions of endogenous excitatory amino acids were examined on the light microscopic level. Repeated manual injections of either glutamate or aspartate (1.8 μmoles/0.5 μ. 1 every 12 hours for 14 days), but not of equimolar GABA, caused neuronal degeneration proximal to the tip of the injection cannula. Nerve cell death was limited to a spherical area with a radius of approximately 0.5 mm. Continuous infusion of these amino acids via osmotic minipumps, at total daily doses identical to those used in the experiments employing manual injections, did not result in lesions in striatum or hippocampus. Attempts using minipump administration of cysteine sulfinate or combinations of glutamate with aspartate, cysteine sulfinate or DL-threo-β-hydroxyaspartate were equally unsuccessful in producing neuronal cell loss. The efficient re-uptake systems for the endogenous amino acids may suffice to continuously remove large quantities of the infused compounds from vulnerable neuronal sites. It appears, however, that these protective mechanisms can be overcome by extremely high local concentrations of glutamate or aspartate. Possible implications for the pathogenesis of human neurodegenerative disorders are discussed.