David Hay

Depletion of 26S Proteasomes in Mouse Brain Neurons Causes Neurodegeneration and Lewy-Like Inclusions Resembling Human Pale Bodies

Ubiquitin-positive intraneuronal inclusions are a consistent feature of the major human neurodegenerative diseases, suggesting that dysfunction of the ubiquitin proteasome system is central to disease etiology. Research using inhibitors of the 20S proteasome to model Parkinsons disease is controversial. We report for the first time that specifically 26S proteasomal dysfunction is sufficient to trigger neurodegenerative disease. Here, we describe novel conditional genetic mouse models using the Cre/loxP system to spatially restrict inactivation of Psmc1 (Rpt2/S4) to neurons of either the substantia nigra or forebrain (e.g., cortex, hippocampus, and striatum). PSMC1 is an essential subunit of the 26S proteasome and Psmc1 conditional knock-out mice display 26S proteasome depletion in targeted neurons, in which the 20S proteasome is not affected. Impairment of specifically ubiquitin-mediated protein degradation caused intraneuronal Lewy-like inclusions and extensive neurodegeneration in the nigrostriatal pathway and forebrain regions. Ubiquitin and α-synuclein neuropathology was evident, similar to human Lewy bodies, but interestingly, inclusion bodies contained mitochondria. We support this observation by demonstrating mitochondria in an early form of Lewy body (pale body) from Parkinsons disease patients. The results directly confirm that 26S dysfunction in neurons is involved in the pathology of neurodegenerative disease. The model demonstrates that 26S proteasomes are necessary for normal neuronal homeostasis and that 20S proteasome activity is insufficient for neuronal survival. Finally, we are providing the first reproducible genetic platform for identifying new therapeutic targets to slow or prevent neurodegeneration.

Is malfunction of the ubiquitin proteasome system the primary cause of α-synucleinopathies and other chronic human neurodegenerative disease?

Neuropathological investigations have identified major hallmarks of chronic neurodegenerative disease. These include protein aggregates called Lewy bodies in dementia with Lewy bodies and Parkinsons disease. Mutations in the alpha-synuclein gene have been found in familial disease and this has led to intense focused research in vitro and in transgenic animals to mimic and understand Parkinsons disease. A decade of transgenesis has lead to overexpression of wild type and mutated alpha-synuclein, but without faithful reproduction of human neuropathology and movement disorder. In particular, widespread regional neuronal cell death in the substantia nigra associated with human disease has not been described. The intraneuronal protein aggregates (inclusions) in all of the human chronic neurodegenerative diseases contain ubiquitylated proteins. There could be several reasons for the accumulation of ubiquitylated proteins, including malfunction of the ubiquitin proteasome system (UPS). This hypothesis has been genetically tested in mice by conditional deletion of a proteasomal regulatory ATPase gene. The consequences of gene ablation in the forebrain include extensive neuronal death and the production of Lewy-like bodies containing ubiquitylated proteins as in dementia with Lewy bodies. Gene deletion in catecholaminergic neurons, including in the substantia nigra, recapitulates the neuropathology of Parkinsons disease.

Why Should We Care about Children's Spirituality?

David Hay discusses the ways that spirituality might be defined and its relationship to morality. He notes the well-intentioned documents produced by the SCAA Values Forum but argues that they have failed to get to grips with the ‘motivating reality of spiritual insight’. Perhaps spiritual awareness cannot be taught as it is part of the biological inheritance that makes us human. If this is the case, and he believes it is, then what the teacher must do is help children become aware of this and reflect on it in the light of the culture of which they are a part. He identifies a number of significant difficulties that have to be overcome before this can be done. In the remainder of the paper he considers the implications of creating such an awareness in children, and details the responsibilities of schools and teachers in this process.

INVESTIGATING CHILDREN'S SPIRITUALITY: THE NEED FOR A FRUITFUL HYPOTHESIS

It is only recently that the spirituality of children as distinct from their religion has appeared as a subject of academic interest. This development permits us to investigate childrens spirituality as an aspect of a more general category than that of religion. Spirituality is characterised here as a natural form of human awareness. Research evidence is offered to demonstrate that the ‘natural’ hypothesis is more resilient to scientific testing than other more reductionist interpretations of spirituality. The conceptual underpinning of a study of childrens spirituality based on the hypothesis is described. The hypothesis appears to offer a fruitful way forward for research.

An evaluation of the long-term outcomes of small-group work for counsellor development

Abstract A questionnaire was designed which enquired into the long-term professional applications and outcomes of Rogerian small-group and Tavistock Group Dynamics training. The 92 respondents were graduates of either a Masters degree or a Diploma in Human Relations or Counselling Studies in a university course where a ‘small-group’ module was a compulsory element of the taught course. Respondents were drawn from graduates of these one-year full-time or two-year part-time courses over a 21-year period. All respondents were involved either directly in professional or voluntary counselling, in the application of counselling skills in their work, or in training in counselling and counselling skills at work. The respondents reported no loss of learning gains over time: ascribed the application of many specific counselling skills to the small-group training process; reported on the affective component of the learning process; and provided only minimal evidence of forms of psychological damage which could be d...

The Cultural Context of Stage Models of Religious Experience

The stage model of religious experience proposed by Edwards and Lowis (this issue), like that of Batson, Schoenrade, and Ventis (1993), has its cultural origins in Puritan and Pietist Christian understandings of religious conversion. Within that context it has validity and explanatory power. It may also have some application to other religious cultures, in particular to those kinds of religious experience that are especially associated with existential crisis. However, even within those versions of Christianity where the model does apply, there are other forms of religious experience that do not appear to have this structure. The major problem with offering a general model of religious experience is that the term has been applied to such a wide variety of human experience and in such a variety of cultures that its meaning has become protean. Attempts to make generalizations about religious experience are more likely to have success when they concentrate on those aspects of the experience that transcend cultural specifics, that is to say the psychological and biological structures that are common to all members of the human species.

Psychologists interpreting conversion: two American forerunners of the hermeneutics of suspicion:

Because of the importance of Puritanism in its history, one of the forms taken by religious Angst at the end of the 19th century in New England was uneasiness about the psychological nature and validity of the conversion experience. Apart from William James and G. Stanley Hall, the leading psychologists who investigated this phenomenon were Edwin Starbuck and James Leuba. Each had a different personal stance with regard to the plausibility of religious belief. In practice their differences of opinion over the psychology of conversion pivoted round the role of sexuality. In the first part of the 20th century their conflicting views brought to the fore themes that were eventually given full expression 40 years later in Paul Ricoeur’s account of the ‘hermeneutics of suspicion’.

Hot and cold technologies for tissue ablation in urology

Increasingly, technology plays an important role in urology, and with this greater use comes the expected increase in regulation. Authors from the UK present a review of the physical properties of ablative technologies, evaluating efficacy and safety, and summarising guidance issued by the National Institute of Health and Clinical Excellence (NICE) where available. There are also reviews from the UK on haematuria, and on the pathology of bladder cancer from an international group of European authors.

Altruism as an Aspect of Relational Consciousness and How Culture Inhibits It

The concept of relational consciousness emerged during an investigation of the plausibility of the hypothesis that Darwinian natural selection underlies the cultural phenomenon of religion. This conjecture originated with Sir Alister Hardy FRS, who was the Head of the Zoology Department in Oxford University between 1946 and 1961 and founder in 1969 of the Religious Experience Research Unit, originally based in Manchester College Oxford. Hardy’s initiative is not well known in the United States, so I will begin with some background information as a preliminary to clarifying my own hypothesis about the connection of relational consciousness with altruism.

Religion under Siege: a Scientific Response: A Lecture given to the Alister Hardy Society meeting at Oxford, 1 December 2007

Last year, shortly before he published The God Delusion, I went to see Richard Dawkins in the Zoology Department in Oxford. I was gathering material for my biography of Alister Hardy and it so happened that Hardy had been head of the Zoology Department when Dawkins arrived there as an undergraduate in 1959. Both were advocates of evolution by natural selection, Hardy defending religion, and Dawkins attacking it on biological grounds drawn from Darwin. Hardy’s deeply religious nature and the juxtaposition with Dawkins’ atheism looked as though it might provide a good story for inclusion in my biography. If I was expecting fireworks, I didn’t get them. Richard remembered Alister as a very loveable man, which indeed he was, and claimed to be entirely unaware of his religious interests. He certainly makes no reference to his old professor in The God Delusion. That is an unfortunate omission, for it means that he never discusses Hardy’s important contribution to the empirical investigation of the biological roots of religion.