Ubiquitin, lysosomes, and neurodegenerative diseases.
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Animals↗
Biomedical subjects
J Lowe
Publications and source records attributed to J Lowe.
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 Alzheimer's 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.
Animals↗
alpha B crystallin expression in non-lenticular tissues and selective presence in ubiquitinated inclusion bodies in human disease.
alpha B crystallin is a lens protein which has homology with the small heat-shock proteins and is also expressed in non-lenticular tissues. Polyclonal antibodies have been raised to a synthetic peptide corresponding to residues 1-10 of alpha B crystallin. The antiserum detects a 20 kDa polypeptide on nitrocellulose replicas after polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate of extracts of heart muscle known to be rich in alpha B crystallin. Staining of normal human tissues reveals immunoreactivity of lens capsular epithelium, skeletal muscle, cardiac muscle, smooth muscle, renal tubular epithelium, Schwann cells, and glial cells, as has been described by other workers. In addition, positive staining of normal thyroid epithelium, colonic epithelium, and stratified squamous epithelium was seen. Tissues known to contain ubiquitinated inclusion bodies were immunostained with the anti-alpha B-crystallin antiserum. Staining of cortical Lewy bodies, astrocytic Rosenthal fibres, and hepatic Mallory bodies was seen, but only a proportion of inclusions were positive. Neurones containing the ubiquitinated inclusions of Alzheimer's disease were only very rarely immunostained and the ubiquitinated inclusions of motor neurone disease were not detected by the antiserum. Reactive astrocytes in cerebral tissues were strongly immunostained. The results suggest that alpha B crystallin is involved in the formation of ubiquitinated inclusion bodies that have associated intermediate filaments and support previous observations on the localization of a brain-specific ubiquitin carboxy-terminal hydrolase which similarly divides ubiquitinated filamentous inclusions in the central nervous system into two main groups.
Alzheimer Disease↗
Lysosomes as key organelles in the pathogenesis of prion encephalopathies.
The causation, structural origin, and mechanism of formation of spongiform lesions in transmissible encephalopathies are unknown. We have used immunogold electron microscopy to locate ubiquitin conjugates, hsp 70, and beta-glucuronidase (markers of the lysosomal compartment) and prion protein (PrP) in both control and scrapie-infected mouse brain. In scrapie-infected brain, lysosomes and lysosome-related structures (multivesicular and tubulovesicular dense bodies) are present in abnormally high numbers in neuronal cell processes. These structures contain PrP, together with the lysosomal markers ubiquitin conjugates, hsp 70, and beta-glucuronidase, which could also be identified spilling from tubulovesicular dense bodies into areas of early rarefaction in neuronal processes; we suggest that these areas of rarefaction are the precursor lesions of spongiform change. We advance the hypothesis that spongiform change is brought about by cytoskeletal disruption in neuronal processes caused by liberation of hydrolytic enzymes from lysosomes overloaded with the abnormal isoform of PrP (PrPsc). We suggest that the lysosomal system is probably acting as the bioreactor for processing of normal PrP to the abnormal isoform. The continuous production of increasing quantities of abnormal PrPsc in lysosome-related bodies will eventually cause disruption of the lysosomal membrane with destruction of the neuronal cytoskeleton and the initiation of vacuolation. Later, death of the cell will be associated with release of the PrPsc isoform into the extracellular environment. Repeated rounds of phagocytosis, lysosomal biogenesis of PrPsc, lysosomal membrane rupture, hydrolytic enzyme release, and neuronal lysis will lead to an exponential increase in cell damage and cell death.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Immunoreactivity to ubiquitin-protein conjugates is present early in the disease process in the brains of scrapie-infected mice.
Brains from mice infected with either the 87V or the ME7 strains of mouse-passaged sheep scrapie were taken at stages during the disease process and immunostained to show the localization of ubiquitin-protein conjugates. In both models, conjugates were seen as fine, dot-like structures; as coarser, granular lesions within or adjacent to neurones; and in areas surrounding plaques. The dot-like structures were visible at 28 days post-ME7 infection and at 55 days in 87V-infected mice. In both models, the extent of immunoreactive changes increased as the disease progressed and terminal infection was as described earlier by us (Lowe et al., J. Pathol 1990; 162: 61-66). The patterns of development of these features were distinctive in two ways: progression from region to region was observable and the density of the pathological lesions grew exponentially as the clinical symptoms appeared. The earliest pathological dot-like structures corresponded temporally with the earliest detection of PrPSC by Western blotting, and immunogold electron microscopic investigation of the dot-like lesions indicated that they were the multi-vesicular, lysosome-related, dense bodies that we have described previously in terminal disease (Laszlo et al., J Pathol 1992; 166: 333-341). Until now, ubiquitin-protein conjugates were seen mainly in inclusion bodies associated with the terminal stages of a range of human degenerative diseases. This study establishes that ubiquitin-protein conjugates accumulate in lysosome-related bodies very early and appear to be intimately related to the pathological processes in the animal disorders that we have studied.
Animals↗
Cerebral contusional tears as a marker of child abuse--detection by cranial sonography.
A series of 6 infants subjected to child abuse is presented in whom contusional tears of subcortical white matter were detected during life by intracranial sonography. The sonographic appearances of this highly pathognomonic marker of shaking injury are described for the first time and their significance discussed. On the basis of our experience we suggest that high resolution cranial sonography is an extremely valuable part of the diagnostic work up in cases of suspected non-accidental injury.
Brain Concussion↗
Ubiquitin, lysosomes and neurodegenerative diseases.
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Brain↗
A role for lysosomes in scrapie pathogenesis.
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Animals↗
Detection of spores of Bacillus anthracis using the polymerase chain reaction.
The polymerase chain reaction (PCR) was used to identify spores of Bacillus anthracis. By using an assay capable of amplifying a 1247-bp fragment from the gene that encodes the edema factor of B. anthracis, as few as 10(3) copies of a plasmid containing the edema factor gene and as few as 2 x 10(4) spores were detected. Subjecting the product of this PCR to a second PCR designed to amplify a 208-bp fragment nested within the 1247-bp product improved detection to a single plasmid copy per PCR and to two spores of B. anthracis per PCR.
Bacillus anthracis↗
Patients' responses to retinitis pigmentosa.
Forty-eight patients with retinitis pigmentosa completed at home a questionnaire about everyday tasks, and recorded their distance visual acuities on reduced Snellen charts. Respondents were asked to assess their own abilities for seven tasks involving visual search and mobility on a 1 to 4 scale. This revealed the relative difficulty of each task for the whole group. Other questions were open-ended to allow respondents to express their individual visual problems and experiences. Several problems came to light that were not amenable to treatment with low vision aids, but should be considered as a guide to the clinician in counseling.
Activities of Daily Living↗
Using a binocular field expander on a wide-field search task.
Five patients with constricted visual fields and good central acuity were fitted with an experimental binocular field expander. They undertook a laboratory visual search task in a stationary horizontal 90 degree field with and without the device. Four of five patients adapted relatively quickly to the inherent optical distortions of the field expander. When this binocular aid was worn search efficiency improved significantly with practice; search time was highly correlated (r = -0.92; p less than 0.01) with information channel capacity in the larger visual field.
Adult↗
Ballooned neurons in several neurodegenerative diseases and stroke contain alpha B crystallin.
alpha B crystallin is a protein which has homology with the small cell stress proteins. A characterized antibody to residues 1-10 of alpha B crystallin was used to immunostain tissues containing ballooned (chromatolytic, achromasic) neurons. The tissues included two cases of classical Pick's disease, one case of dementia with swollen achromasic neurons in the cortex, two cases of Alzheimer's 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-alpha B crystallin showed strong diffuse cytoplasmic immunoreactivity 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 alpha B crystallin in ballooned neurons, together with previous data which also indicate its close association with intermediate filaments, suggest that alpha B crystallin may be involved in aggregation and remodelling of neurofilaments in disease. The presence of alpha B 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.
Alzheimer Disease↗
The floating hip. Ipsilateral pelvic and femoral fractures.
A consecutive series is reported of 17 patients who underwent early surgical treatment for acetabular or unstable pelvic fractures associated with ipsilateral fractures of the femur. Treatment included external and internal fixation, and required careful consideration of the surgical approach and the positioning of the patient. The multiple injuries sustained by these patients required simultaneous procedures by several surgical teams. All the femoral fractures were internally fixed at the initial operation and eight patients had primary definitive treatment of all their other fractures as well. In nine patients the definitive treatment of their other fractures was delayed for an average of 11 days. There were no deaths, and no serious infections. The long-term morbidity resulted from the associated injuries and not from the pelvic or femoral fractures.
Acetabulum↗
The risk of severity of limb injuries in racing thoroughbred horses.
A retrospective study was carried out to identify factors which predisposed Thoroughbred horses to severe injuries, as compared to less severe injuries, while racing on New York Racing Association (NYRA) tracks during the period of January 1986 to June 1988. A severe injury was defined as an injury which led to humane destruction of the horse. A less severe injury was defined as a horse which didn't race within 6 months following a muscular, ligament, tendon, or skeletal injury on the racetrack. The data were obtained from the Horse Identification Department records kept by the Chief Examining Veterinarian of NYRA and included 55 severely injured horses and 245 less severely injured horses. Multiple logistic regression analysis was used to identify factors associated with the risk of severe injuries compared to less severe injuries in those horses. There was a significant association between track and the risk of severe injury (horses raced on Belmont and Saratoga were more likely to develop a severe injury compared to horses raced on Aqueduct Main). The track surface was also associated with the risk of severe injury (horses raced on a firm turf had a significantly lower risk of severe injury associated with the track was significantly modified by the track condition (horses raced at Belmont when it was muddy had a significantly increased risk compared to Aqueduct dirt). Horses were more likely to experience severe injury in the early part of the race (less than or equal to 6 furlongs) than the latter part of the race (greater than 6 furlongs). The risk of severe injury decreased with the age of the horse.
Age Factors↗
Ubiquitin in health and disease.
Studies in recent years have shown that ubiquitin has increasingly important functions in eukaryotic cells; roles which were previously not suspected in healthy and diseased cells. The interplay between molecular pathological and molecular cell biological findings has indicated that ubiquitin may be pivotal in the cell stress response in chronic degenerative and viral diseases. Furthermore, the studies have led to the notion that ubiquitination may not only serve as a signal for nonlysosomal protein degradation but may be a unifying covalent protein modification for the major intracellular protein catabolic systems; these can act to identify proteins for cytosolic proteinases or direct intact and fragmented proteins into the lysosome system for breakdown to amino acids. This unifying role could explain why ubiquitin is restricted to eukaryotic cells, which possess extensive endomembrane systems in addition to a nuclear envelope. Protein ubiquitination is a feature of most filamentous inclusions and certain other intracellular conglomerates that are found in some degenerative and viral diseases. The detection of ubiquitin-protein conjugates is not of great diagnostic importance in these diseases. Protein ubiquitination is not only essential for the normal physiological turnover of proteins but appears to have been adapted as part of an intracellular surveillance system that can be activated by altered, damaged, or foreign proteins and organelles. The purpose of this system is to isolate and eliminate these noxious structures from the cell: as a cytoprotective mechanism this appears to have evolved in the cell akin perhaps to an 'intracellular immune system'. Other heat shock proteins such as hsp 70 may be involved in this process. It is apparent that ubiquitin has a role in embryonic development. Protein ubiquitination is presumably involved in the reorganisation of cytoplasm that accompanies cell differentiation. Ubiquitin is also necessary for the gross intracellular degradative processes which are consequent upon programmed cell death. Cell elimination is of key importance for a number of developmental morphogenetic changes. An understanding of the molecular details of these processes will no doubt provide further insights into the wide ranging roles of ubiquitin in the life process. As it says in the book 'Ubiquitin'; there is no doubt that ubiquitin is a 'lucky' protein. It is lucky in many ways: lucky for scientific progress, lucky for biomedical scientists and lucky for life! If you have not already done so, why don't you get lucky and look for a role for ubiquitin in your experimental system. As Avram Hershko has said "there is plenty to go round"!
Animals↗
Immunogold localisation of ubiquitin-protein conjugates in primary (azurophilic) granules of polymorphonuclear neutrophils.
Ubiquitin-protein conjugates are found in the primary (azurophilic) lysosome-related granules but not in the secondary (specific) granules in mature polymorphonuclear neutrophils prepared from bone marrow. This is the first reported demonstration of ubiquitin-protein conjugates in lysosome-related membrane-bound vesicles in granulocytes and complements our previous findings of ubiquitinated proteins in lysosomes of fibroblasts. The significance of the selective presence of conjugates in only one of the two main types of neutrophil granules remains to be elucidated but may relate to the presence of the complement of acid hydrolases, including proteases, in the azurophilic granules compared to the specific granules. Ubiquitin-protein conjugates may enter the primary granules during neutrophil maturation by an autophagic process or by a heterophagic process during the fusion of phagosomes with primary granules. Alternatively protein ubiquitination may be involved in granule biogenesis.
Animals↗
Haemorrhagic shock encephalopathy and sudden infant death.
In 2 pairs of non-identical twins, haemorrhagic-shock encephalopathy syndrome developed in 1 co-twin while the other died of sudden infant death syndrome. The twin pairs were aged 3 and 4 months, respectively, and no cause was identified. We suggest that stress protein deficiency may underlie both syndromes.
Acute Disease↗