Proteasome degradation

Covalent binding of ubiquitin to proteins marks them for degradation by the 26S proteasome (Figure 2), an enzymatic complex with a native molecular weight of approximately 2,000 kDa11. The 26S proteasome includes two major particles a 20S particle, known as the 20S proteasome, which is the catalytic core, and a 19S particle, known as PA700, which is the regulatory component. Association between the two particles in the cell is a dynamic process and requires ATP-hydrolysis. The 20S proteasome...

The Calpain System In Neuromuscular Diseasethe Muscular Dystrophies

The Muscular Dystrophy Association(MDA) supports research in over 40 different kinds of muscular dystrophies ranging from diseases caused by defects in mitochondrial function and deficiencies in particular metabolic enzymes such as phosphorylase or maltase to endocrine abnormalities and diseases of the peripheral nerves (Charcot-Marie-Tooth disease, Friedreich's ataxia) to the more widely recognized Duchenne and Becker's muscular dystrophy. Many but not all of these muscular dystrophies are...

Cellmediated myelinolysis in CNS demyelination

The predominant cellular route of myelin breakdown is via macrophages, although polymorphonuclear leukocytes participate in acute haemorrhagic lesions, and Schwann cells are involved in the PNS. Astrocytes probably also contribute, particularly in later stages as they are observed with ingested myelin in MS plaques60. Activated macrophages possess a wide range of receptors which can effect myelin endocytosis61. In vitro myelin is efficiently taken up by macrophages in the absence of specific...

Cathepsins And Neurological Diseases Brain Tumors

Matrix metalloproteinases, serine proteases, aspartate proteases and cysteine lysosomal proteases individually, or in concert with each other contribute to the localized destruction of extracellular matrix (ECM), which is a salient feature of malignant tumors. Overexpression, ectopic expression of cysteine lysosomal proteases, and changes in their processing have been observed in malignant tumors of different origin48 49. Of the growing number of members of the family of cysteine cathepsins,...

Calpain Activity And Expression In Experimental Allergic Encephalomyelitis

EAE is an autoimmune inflammatory disease induced in animals - most commonly rabbits, guinea pigs, monkeys, mice and Lewis rats - by injection of an emulsified suspension of whole CNS tissue, white matter, myelin, PLP or MBP, together with Freund's complete adjuvant (FCA)106-110. The animals progressively lose weight followed by development of paralysis at 10 to 12 days after challenge. Perivascular cuffing with infiltrating lymphocytes, monocytes and plasma cells, can be observed by light...

Proteases In Demyelination In Vitro

The relative metabolic stability of myelin might be expected to impart a significant degree of protection from proteolytic attack. However, there are a number of pathological conditions, which are characterized by demyelination, perpetrated generally by the proteolytic and lipolytic enzymes of phagocytic cells. While useful information can be gained from in vitro assays of proteolytic activity the potential enzymatic capacity may not bear a direct relationship to activity in vivo. Regulatory...

Participation Of Lensspecific Calpains In Lens Maturation And Cataract Formation

Until recently, cataract formation in rodent models as discussed above was thought to be solely due to m-calpain. This was because abundant levels of m-calpain were found in rodent lenses16. However, recent use of RT-PCR with degenerate primers for the active site of calpain17 and the increased sensitivity of casein zymography2 demonstrated the presence of the lens-specific calpains termed Lp82 and Lp85. In young mice, Lp82 is actually the dominant calpain over the ubiquitous m- and...

Proteases In Demyelination In Vivo

The biochemical changes in MS and experimental allergic encephalomyelitis (EAE) have been documented extensively6,24. In the demyelinated plaque myelin proteins and lipids are almost completely replaced by the glial fibrillary acidic protein of astrocytic fibrils. In lesions with ongoing demyelination myelin is apparent within macrophages in the hypercellular zone between normal-appearing white matter and the plaque centre and histochemical, immunocytochemical and biochemical analyses show...

Calpain Activity And Expression In Multiple Sclerosis

The findings of increased calpain expression in animals with EAE suggested this enzyme may also be upregulated in MS. Calpain activity in postmortem tissue form human MS patients was measured by the production of calpain-specific degradation products. Calpain degrades the 230 kD subunit of fodrin to produce a 150 kD fragment which is recognized by the antibody used in this study. Although production of the 150 kD fodrin fragment was marginally increased in white matter from Alzheimer's patients...

Synthetic Inhibitors Of Cathepsins

Inhibitors of putative target proteases are used as fundamental tools to investigate the physiological and pathological implications of these enzymes. Measurable effects of protease inhibitors on functional parameters of brain pathology such as ischemic neuronal cell death or ataxia and biochemical observations of cleavage events on selected substrates are frequently the only indications that a certain protease class or an individual enzyme is involved. The implication of an individual protease...

Preface

Researchers seeking problems that offer more hope of success often avoid subjects that seem to be difficult to approach experimentally, or subjects for which experimental results are difficult to interpret. The breakdown part of protein turnover in vivo, particularly in nervous tissue, was such a subject in the past - it was difficult to measure and difficult to explore the mechanisms involved. For factors that influence protein metabolism, it was thought that protein content, function, and...

References

O'Shannessy, R.K. Quarles, K. Suzuki, and T. Miyatake, Myelin- associated calpain II, J. Neurochem. 51 803 (1988). 2. J.F. Hallpike, Enzyme and protein changes in myelin breakdown, in Progress in Histochemistry and Cytochemistry, Vol. 3, W. Grauman, A. Lajtha, A.G.E. Pearse, and T.H. Scheibler, eds., Gustav Fischer Verlag, Stuttgart (1982). 3. P. W. Lampert, Demyelination and remyelination in experimental allergic encephalitis Further electron microscopic...

Notchsignaling And The Unfolded Protein Response

Presenilins recently were found to influence turnover of Notch-r and components of the 'UnfoldedProtein Response' thus reinforcing their roles as putative Asp-proteases (see Fig. 6). While they are spatially separated in cells, the binding of PS to Notch at the ER membrane provides a potential pathway for targeting to the plasma membrane, the site for Notch processing. Mutation of PS aspartyl residues, while not blocking trafficking, prevents Notch processing174,175. Notch-r is formed by...