Huntington's Disease

Huntington''s disease (HD) is the most common inherited neurodegenerative disease and is characterized by uncontrolled excessive motor movements and cognitive and emotional deficits. The mutation responsible for HD leads to an abnormally long polyglutamine (polyQ) expansion in the huntingtin (Htt) protein, which confers one or more toxic functions to mutant Htt leading to neurodegeneration. The polyQ expansion makes Htt prone to aggregate and accumulate, and manipulations that mitigate protein misfolding or facilitate the clearance of misfolded proteins tend to slow disease progression in HD models. This article will focus on HD and the evidence that it is a conformational disease.     

Bridging the Valley of Death of therapeutics for neurodegeneration

Neurodegenerative diseases are the sixth leading cause of death in the US. The market for disease-modifying drugs is enormous, but no drug exists. Academic scientists are increasingly pursuing the discovery and development of therapeutics. Their progress could potentially reduce the risk of failure sufficiently to warrant greater industry investment and movement of leads into clinical trials. Here we consider the many obstacles to the development of therapeutics for neurodegenerative disease within academia, with a special focus on organizational issues.     

The New International Standards for Life Cycle Assessment: ISO 14040 and ISO 14044

Background, Aims and Scope The development of the international standards for life cycle assessment (ISO 14040:1997, ISO 14041:1999, ISO 14042:2000, ISO 14043:2000) was an important step to consolidate procedures and methods of LCA. Their contribution to the general acceptance of LCA by all stakeholders and by the international community was crucial. Currently, the process of the revision of this first generation of LCA standards is close to completion. The paper explains the outline as well as formal and technical changes of the coming new international standards of LCA, i.e. the new ISO 14040 and ISO 14044. Methods The paper refers to life cycle assessment based on the international standards for LCA (ISO 14040:1997, ISO 14041:1999, ISO 14042:2000, ISO 14043:2000). The content relates to the Final Draft International Standard (FDIS) versions of the new ISO 14040 and ISO 14044. Results and Discussion With the publication of the two new standards, ISO 14040 and ISO 14044, the existing four standards ISO 14040:1997, ISO 14041:1999, ISO 14042:2000 and ISO 14043:2000 are technically revised, cancelled and replaced. According to the scope of the revision, the core part of the technical contents remains unchanged. Improved readability and the removal of errors and inconsistencies was the focus of the revision. However, despite the fact that the main technical content was confirmed to be still valid, some relevant formal and technical changes were made. On the technical side these include e.g. the addition of principles for LCA, the addition of an annex about applications, the addition of several definitions (e.g. product, process, etc.), clarifications concerning LCA intended to be used in comparative assertions intended to be disclosed to the public, clarifications concerning the critical review panel, clarifications concerning system boundary, etc. On the formal side, changes include the reduced number of standards, a reduced number of annexes, a reduced number of pages that contain requirements, alignment of definitions and clarification of compliance with the standards. Conclusion The two new standards, ISO 14040 and ISO 14044, reconfirm the validity of the main technical content of the previous standards. Errors and inconsistencies were removed and the readability was improved. The added technical content is in line with the previous requirements and serves mainly as a clarification of the technical content. The unanimous vote on the Draft International Standard versions proved that this was achieved on the basis of the broadest possible international consensus. Recommendation and Outlook Currently the national member bodies undertake the final voting on the FDIS-versions of the standards. Based on the voting results at the previous stages of the documents, a positive result is expected. The publication of the new international standards for life cycle assessment (ISO 14040 and ISO 14044) is expected around mid-2006. For the sake of the international and stakeholder acceptance of LCA, it is recommended that the new standards serve as core reference documents for the users and practitioners of LCA.     

Single Neuron Ubiquitin-Proteasome Dynamics Accompanying Inclusion Body Formation in Huntington Disease

The accumulation of mutant protein in intracellular aggregates is a common feature of neurodegenerative disease. In Huntington disease, mutant huntingtin leads to inclusion body (IB) formation and neuronal toxicity. Impairment of the ubiquitin-proteasome system (UPS) has been implicated in IB formation and Huntington disease pathogenesis. However, IBs form asynchronously in only a subset of cells with mutant huntingtin, and the relationship between IB formation and UPS function has been difficult to elucidate. Here, we applied single-cell longitudinal acquisition and analysis to monitor mutant huntingtin IB formation, UPS function, and neuronal toxicity. We found that proteasome inhibition is toxic to striatal neurons in a dose-dependent fashion. Before IB formation, the UPS is more impaired in neurons that go on to form IBs than in those that do not. After forming IBs, impairment is lower in neurons with IBs than in those without. These findings suggest IBs are a protective cellular response to mutant protein mediated in part by improving intracellular protein degradation.Huntington disease (HD)⁴ is a progressive incurable neurodegenerative disorder caused by the expansion of a polyglutamine (polyQ) stretch in the N-terminal end of the huntingtin (htt) protein above a threshold length of ∼36 (1). The deposition of polyQ-expanded aggregated mutant htt in inclusion bodies (IBs) is a hallmark of HD, and IBs are found in human post-mortem samples, transgenic mouse brain, and cell-culture models (2). The accumulation of ubiquitinated proteins in IBs has implicated the ubiquitin-proteasome system (UPS) in the pathogenesis of HD, amyotrophic lateral sclerosis, Parkinson disease, and polyQ-mediated disorders (3).The UPS is a major pathway of intracellular protein degradation. After a series of three reactions, each catalyzed by a different set of enzymes, ubiquitin, a 76-amino acid polypeptide, forms an isopeptide bond with the amino group of lysine residues on substrate proteins. Several lysine residues within ubiquitin are sites for more ubiquitin additions. Once a protein accumulates four or more ubiquitins, it is efficiently targeted to the proteasome for degradation. The proteasome binds polyubiquitinated substrates and hydrolyzes ubiquitin isopeptide bonds, releasing ubiquitin moieties before degrading substrate proteins through chymotrypsin-like, trypsin-like, and post-glutamyl peptidase activities (3).Increased polyubiquitin levels and changes in ubiquitin linkages accompany the accumulation of UPS substrates in the brains of HD patients and transgenic mice and in cellular HD models (4). UPS substrates accumulate throughout the cell in polyQ models, even before IB formation (5, 6). This has added to the confusion over whether polyQ expansion leads to toxicity through direct impairment of proteasomal degradation. Proteasomes have been reported to cleave polyQ stretches efficiently (7), inefficiently (8), or essentially not at all (9). In vivo, polyQ-dependent degeneration occurs with no detectable proteasome inhibition (10, 11) or is tightly linked to it (12, 13). The inability of some studies to detect UPS impairment in HD models may be due to the limited sensitivity of conventional approaches to identify cell-to-cell variations in UPS function.The relationship between IB formation and UPS function has been difficult to determine. Protein turnover in cells with IBs is evidently reduced and accompanied by the accumulation of cellular proteins (14–16); HEK293 cells containing mutant htt IBs have a greater degree of UPS impairment than those without IBs (5). Proteasome subunits and heat shock proteins colocalize with IBs, but it is unclear if this colocalization facilitates protein delivery or unfolding at the mouth of active proteasomes, or if it harms proteasome function by sequestering essential cellular machinery (18). Some IBs are relatively static (8, 25), but the proteins in others are dynamically exchanged with cytoplasmic and nuclear pools (19, 20).UPS function is critical to cellular homeostasis. Deletion of one of the two inducible polyubiquitin genes in mice leads to lower intracellular ubiquitin levels in germ cells and hypothalamic neurons. These same populations undergo cell-cycle arrest and hypothalamic neurodegeneration, respectively (22, 23). Cell lines expressing mutant huntingtin accumulate ubiquitinated proteins and undergo cell-cycle arrest in G2/M (5). In neurons, UPS impairment may lead to cell death through an accumulation of signals for apoptosis, a decrease in NF-κB signaling, sensitization to other toxic stimuli, remodeling of synapses, retraction of neurites, or other unidentified mechanisms (24). The effect of UPS impairment depends on cell type and cell cycle, and the relationship between UPS impairment and striatal neuronal survival is largely unknown.Diffuse species of mutant htt induce IB formation and neuronal death in a protein concentration-dependent manner (2). IB formation delays neuronal death, suggesting that IB formation helps neurons cope with toxic diffuse mutant htt. Whether the effect of IB formation on survival is mediated through UPS function has been difficult to determine. IB formation and neuronal death occur asynchronously in overlapping but distinct subsets of neurons that express mutant htt. The observation that IB formation is not required for UPS impairment also complicates population analysis (6, 26).To explore this problem, we applied single-cell analysis. We tracked single neurons over their entire lifetimes, gaining spatial and temporal resolution while simultaneously monitoring IB formation, UPS inhibition, and neuronal toxicity.     

Life-LCA: assessing the environmental impacts of a human being—challenges and perspectives

Purpose

The life-cycle assessment (LCA) method is typically applied to products, but the potential and demand for extending its use also to other applications are high. In this respect, this paper proposes an LCA concept to be used for the assessment of human beings as new study objects, namely Life-LCA. Key challenges of such a new approach and potential solutions for those are identified and discussed.

Methods

The Life-LCA concept was developed based on a detailed desktop research. Several Life-LCA-specific challenges were identified and categorized under three research questions. One of these questions focusses on the conceptual design of a Life-LCA method while the others are addressing operational issues, which are the definition of the new study system and the practical assessment of complex human consumption behaviors. Methodological solutions are proposed, e.g., based on suggestions provided in the existing methods product LCA and organizational LCA (O-LCA).

Results and discussion

Conceptual challenges arise from the general diversity, complexity, and temporal development of human lives and consumption behaviors. We introduce Life-LCA as a two-dimensional method that covers both, the new human life cycle (dimension 1) and the life cycle of the consumed products (dimension 2). Furthermore, the two types Individual Life-LCA and Lifestyle-LCA are differentiated. Especially, the definition of a general system boundary for Life-LCA and data collection and evaluation face many operational challenges. For example, the social behavior of human beings is a new factor to be considered which causes new allocation problems in LCA. Moreover, the high demand for aggregated LCA data requires specific rules for data collection and evaluation as well as a new bottom-up product clustering scheme.

Conclusions

Life-LCA, either used for the assessment of individual lives or lifestyles, has the potential to raise environmental awareness of people by making their specific environmental impacts comprehensively measurable and thus, tangible. However, many challenges need to be solved in future interdisciplinary research to develop a robust and applicable method. This paper conceptualizes such an approach and proposes solutions that can serve as a framework for ongoing method development.

     

Addressing water quality in water footprinting: current status,methods and limitations

Purpose

In contrast to water consumption, water pollution has gained less attention in water footprinting so far. Unlike water scarcity impact assessment, on which a consensus has recently been achieved, there is no agreement on how to address water quality deterioration in water footprinting. This paper provides an overview of existing water footprint methods to calculate impacts associated with water pollution and discusses their strengths and limitations using an illustrative example.

Methods

The methods are described and applied to a case study for the wastewater generated in textile processing. The results for two scenarios with different water quality parameters are evaluated against each other and the water scarcity footprint (WSF). Finally, methodological aspects, strengths and limitations of each method are analysed and discussed and recommendations for the methods application are provided.

Results and discussion

Two general impact assessment approaches exist to address water quality in water footprinting: the Water Degradation Footprint (WDF) calculates the impacts associated with the propagation of released pollutants in the environment and their uptake by the population and ecosystem, while the Water Availability Footprint (WAF) quantifies the impacts related to the water deprivation, when polluted water cannot be used. Overall, seven methods to consider water quality in water footprinting were identified, which rely upon one or a combination of WDF, WAF and WSF. Methodological scopes significantly vary regarding the inventory requirements and provided results (a single-score or several impact categories). The case study demonstrated that the methods provide conflicting results concerning which scenario is less harmful with regard to the water pollution.

Conclusions

This paper provides a review of the water pollution assessment methods in water footprinting and analyses their modelling choices and resulting effects on the WF. With regard to the identified inconsistencies, we reveal the urgent need for a guidance for the methods application to provide robust results and allow a consistent evaluation of the water quality in water footprinting.

     

Spatial and Temporal Attention Modulate the Early Stages of Face Processing: Behavioural Evidence from a Reaching Paradigm

A presently unresolved question within the face perception literature is whether attending to the location of a face modulates face processing (i.e. spatial attention). Opinions on this matter diverge along methodological lines – where neuroimaging studies have observed that the allocation of spatial attention serves to enhance the neural response to a face, findings from behavioural paradigms suggest face processing is carried out independently of spatial attention. In the present study, we reconcile this divide by using a continuous behavioural response measure that indexes face processing at a temporal resolution not available in discrete behavioural measures (e.g. button press). Using reaching trajectories as our response measure, we observed that although participants were able to process faces both when attended and unattended (as others have found), face processing was not impervious to attentional modulation. Attending to the face conferred clear benefits on sex-classification processes at less than 350ms of stimulus processing time. These findings constitute the first reliable demonstration of the modulatory effects of both spatial and temporal attention on face processing within a behavioural paradigm.