Amyotrophic lateral sclerosis pathology

Kato, S. etal. Amyotrophic lateral sclerosis, in D. Dickson (ed.), Neurodegeneration - The Molecular Pathology of Dementia and Movement Disorders. Basel ISN Neuropathology Press, 2003, pp. 350-368. 

Dal Canto, M. C. and Gurney, M. E. Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am. J. Pathol. 145 1271-1280, 1994. 

CBP displays important functions during central nervous system development and increasing evidence suggests that CBP loss of function is involved not only in RTS but also in further neurodegenerative diseases, such as polyglutamine-related pathologies (Fiuntington s disease), Alzheimer s disease and amyotrophic lateral sclerosis [9]. 

The pathological characteristic of Parkinson s disease is the selective degeneration of dopamine neurons in the pars compacta of the substantia nigra. The mechanism for the loss of neurons remains to be elucidated, and recently apoptosis has been proposed as a death process in Parkinson s disease. For example, the level of a product of the oxidative stress, 4-hydroxy-2-nonenal protein adduct, was found to increase in the nigral neurons of parkinsonian brains. Peroxynitrite (see Figure 13.6) has been proposed to be involved in the neuronal cell death in some neurodegenerative diseases, such as amyotrophic lateral sclerosis. 

Coenzyme Q10 and vitamin E are found in wheat germ. Furthermore, studies in mice have shown that administration of coenzyme Q10 elevate the level of mitochondrial a-tocopherol (Lass et al., 1999). Beal and his colleagues (2002) investigated the potential usefulness of coenzyme Q10 in animal models of PD, amyotrophic lateral sclerosis (ALS), and HD. It has been demonstrated that coenzyme Q10 can protect against striatal lesions produced by the mitochondrial toxins malonate and 3-nitropropionic acid. These toxins have been utilized to model the striatal pathology, which... 

Hirano, A., Malamud, N., Elizan, T. S. and Kurland, L. T. (1966) Amyotrophic lateral sclerosis and Parkinsonism-dementia complex on Guam. Further pathologic studies. Arch Neurol 15, 35-51. 

Dal Canto, M. C., and Gurney, M. E. (1994). Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am.J. Pathol. 145, 1271-1279. Daniels, K. K., and Vickroy, T. W. (1999). Reversible activation of glutamate transport in rat brain glia by protein kinase C and an okadaic acid-sensitive phosphoprotein phosphatase. Neurochem. Res. 24, 1017-1025. 

Pathological activation of glutamate receptors is a common feature and one of the primary causes of neuronal death in acute neuronal injury (such as trauma, epilepsy, and brain ischemia) and chronic neurodegenerative diseases (such as Parkinson s disease, Alzheimer diseases, amyotrophic lateral sclerosis, and AIDS dementia) (Choi, 1988 Doble, 1999 Lipton and Rosemberg, 1994). In particular, elevation of extracellular glutamate level is a key factor in the development of neuronal damage under ischemic conditions. 

Because of the instability of peroxynitrite under physiological conditions, the detection of 3-nitrotyrosine (NC>2-Tyr) has become a biochemical marker for the presence of peroxynitrite in pathophysiological processes. The biological significance of tyrosine nitration is a subject of great interest, because extensive evidence supports the formation of nitrotyrosine in vivo in diverse pathological conditions such as heart diseases, chronic inflammation and autoimmune diseases, cancer, Parkinson s disease, Alzheimer s disease, multiple sclerosis, amyotrophic lateral sclerosis, and ischemia-reperfusion injury [11]. 

Nitration of phenolic compounds leads to the formation of 3-nitrotyrosine (molar extinction coefficient = 14 400 at 428 nm) (Figure 7.11). The reaction is very specific for phenolic compounds. Chemical nitration of functionally important tyrosine residues by tetranitromethane has often been found to inactivate or alter the enzyme properties. It was only after the detection of in vivo nitrotyrosine formation under inflammatory conditions that the physiological aspects of nitrotyrosine metabolism came to light. Abundant production (1-120 /uM) of nitrotyrosine has been recorded under a number of pathological conditions such as rheumatoid arthritis, liver transplantation, septic shock, and amyotrophic lateral sclerosis (Balabanli etal. 1999). 

CD spectroscopy has also provided valuable insight into the chemical stability and chemical denaturation of proteins. A recent study by Rumfeldt etal. examines the guanidinium-chloride induced denaturation of mutant copper-zinc superoxide dismutases (SODs). These mutant forms of the Cu, Zn-SOD enzyme are associated with toxic protein aggregation responsible for the pathology of amyotrophic lateral sclerosis. In this study, CD spectroscopy was used in conjunction with tryptophan fluorescence, enzyme activity, and sedimentation experiments to study the mechanism by which the mutated enzyme undergoes chemical denaturation. The authors found that the mutations in the enzyme structure increased the susceptibihty of the enzyme to form partially unfolded destabilized monomers, rather than the stable metaUated monomer intermediate or native metallated dimer. 

Tandan, R. and Bradley, W.G. (1985a) Amyotrophic lateral sclerosis Part 1. Clinical features, pathology, and ethical issues in management. Ann. Neurol. 18 271-280. 

AMYOTROPHIC LATERAL SCLEROSIS CLINICAL FEATURES AND PATHOLOGY... 

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