R. J. Mayer

Ballooned neurons in several neurodegenerative diseases and stroke contain αB crystallin

αB crystallin is a protein which has homology with the small cell stress proteins. A characterized antibody to residues 1–10 of αB crystallin was used to immunostain tissues containing ballooned (chromatolytic, achromasic) neurons. The tissues included two cases of classical Picks disease, one case of dementia with swollen achromasic neurons in the cortex, two cases of Alzheimers disease with large numbers of ballooned neurons, two cases of motor neuron disease, four cases of cortico‐basal degeneration, and four cases with areas of brain showing swollen neurons adjacent to recent cerebral infarcts. The anti‐αB crystallin showed strong diffuse cytoplasmic immunoreac‐tivity of swollen cortical neurons in all the diseases. Astrocytes and oligodendroglial cells were also stained in normal tissues as previously described. Weak diffuse immunoreactivity with an antibody to ubiquitin‐conjugates was also seen in the swollen neurons from cases of neurodegenerative disease but not following infarction. Ballooned neurons have been shown to contain phosphorylated neurofilament epitopes not normally present in the perikaryonal region. The presence of αB crystallin in ballooned neurons, together with previous data which also indicate its close association with intermediate filaments, suggest that αB crystallin may be involved in aggregation and remodelling of neurofilaments in disease. The presence of αB crystallin in neurons at the edge of areas of cerebral infarction is likely to reflect cells which are regenerating following damage; its detection may therefore be a marker for such cells. On a practical level, the antibody greatly facilitates the localization of such abnormal neurons in diagnostic histology.

Protein processing in lysosomes : the new therapeutic target in neurodegenerative disease

A little recognised feature of neurons is their large complement of lysosomes. Studies of the accumulation of the abnormal isoform of the prion protein (PrPSC) in the prion encephalopathies and the formation of beta/A4 protein from its precursor in Alzheimers disease suggest that generation of these key proteins takes place in lysosome-related organelles. The release of hydrolytic enzymes from lysosomes may be a primary cause of neuronal damage. Although molecular genetic approaches have identified protein mutations central to the main neurodegenerative disease, cell biological observations are now beginning to unravel the intracellular pathways involved in the molecular pathogenesis of neurodegeneration: as a result, it is now appropriate to consider therapeutic manipulation of the lysosomal system as an approach to treatment.

Gankyrin, the 26 S proteasome, the cell cycle and cancer

The known molecular players in cell-cycle control are much studied, not only to learn more about this intricate system, but also to understand the molecular features of oncogenic transformation. Infrequently, new players are discovered that change the interpretation of cell-cycle control. Gankyrin is one such player and was discovered in yeast two-hybrid screens as a new proteasomal subunit that interacts specifically with the S6b (rpt3) AAA (ATPase associated with various cellular activities) ATPase, which, with five other AAAs, are present in the so-called base of the 19 S regulator of the 26 S proteasome. Gankyrin is also the first liver oncogene. Gankyrin is found in other complexes that contain Rb (retinoblastoma protein) and the ubiquitin protein ligase Mdm2 (murine double minute 2). Gankyrin increases the hyperphosphorylation of Rb and therefore activates E2F-dependent transcription of DNA synthesis genes. Additionally, gankyrin, by binding to Mdm2, increases the ubiquitylation and degradation of p53 and prevents apoptosis. Gankyrin controls the functions of two major tumour suppressors and, when overexpressed, causes hepatocellular carcinoma.

Glucose metabolism in the mucosa of the small intestine enzymes of the glycolytic pathway

Abstract 1. 1. The activities of all the enzymes associated with the production of lactic acid from glucose were measured in the particle-free supernatant prepared from the mucosa of rat small intestine. The enzymes of lowest activity were hexokinase and aldolase. 2. 2. The only enzymes whose total and specific activities were significantly depressed after starvation for 36 hours were hexokinase, phosphofructokinase, and pyruvate kinase.

Symposium: cell stress genes and the nervous system

The study of cell stress genes and their resulting proteins has drawn together workers with a remarkably wide set of interests in human, animal, insect, plant and yeast biology. This is because the functions of stress gene products ramify into processes as diverse as cell proliferation, cellular differentiation, intracellular protein trafficking, cell proteolysis, antigen presentation, autoimmunity, cell repair and protection against cell damage. Despite this broad biological spread, the cell stress genes and their products are some of the most conserved in evolution. One important reason why there has been rapid advances in the understanding of this group of genes is because results from one biological system can quickly be transferred to another: findings in yeast can soon be applied to man. The cell stress, or heat shock response is characterized by the activation of a set of genes, termed cell stress genes, in response to environmental stimuli. Early work uncovered that this class of gene is induced by diverse environmental stimuli; for example heat, cold, irradiation, toxins, trauma, and ischaemia. This cell stress activates a so-called heat shock transcription factor (HSF), normally present in an inactive form within cells. The activated HSF then binds to a regulatory element (heat shock element or HSE) and activates transcription of the respective gene. Thus it is the presence of a heat shock regulatory element in the gene promoter region which characterizes a heat shock gene [l]. The main subgroups of heat shock protein are referred to by size, proteins within each group often being dissimilar in structure: 105 kDa, 90 kDa, 70 kDa, 25-30 kDa [ 2 , 31. The most studied of the heat shock proteins are those in the 70kDa class, grouped as the hsp70 proteins, and ubiquitin. Many of the heat shock proteins are expressed at low levels in normal cells and are upregulated following cell stress. In normal cells the proteins are used to assist protein folding and translocation, many being so-called chaperone proteins [4-61. In response to stress. the higher expression of cell stress proteins has a role in cell protection; including the reorganization of damaged or malfunctioning proteins to restore activities or the disposal of the proteins in intracellular protriolytic systems. The cell stress response in the nervous system has been the subject of several recent reviews [7-12 1. The first scientific conference devoted to the study of ‘cell stress genes and the nervous system’ was held 6-8 April 1995 at the University of Nottingham Medical School in England. This meeting, organized by John Mayer (University of Nottingham) and Ian Brown (University of Toronto) presented a comprehensive overview of activity on the expression and function of cell stress genes in the nervous system. The conference represented a ‘followup’ of a book ‘Heat Shock Proteins in the Nervous System’ edited by Mayer and Brown [ 131. The scientific programme of the Nottingham hleeting, which was composed of 18 invited speakers, plus poster sessions, was divided into six topics: (1) stress response, (2) neurotrauma and injury, ( 3 ) ischaemia and seizures, (4) developmental expression, (5) cell stress proteins in neurodegenerative disease, and (6) cell stress proteins in multiple sclerosis. The following symposium hils been drawn to cover these areas and illustrate how the cell stress genes are fundamental to the pathogenesis of several major diseases of the nervous system. It is to be expected that further insights will allow modulation of this response with important implications for therapy in several of the diseases which are. as yet incurable.