HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS

A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration. Cellular mechanisms for degrading misfolded protein include the ubiquitin-proteasome system (UPS), the main non-lysosomal degradative pathway for ubiquitinated proteins, and autophagy, a lysosome-mediated degradative pathway. The UPS and autophagy have long been viewed as complementary degradation systems with no point of intersection. This view has been challenged by two observations suggesting an apparent interaction: impairment of the UPS induces autophagy in vitro, and conditional knockout of autophagy in the mouse brain leads to neurodegeneration with ubiquitin-positive pathology. It is not known whether autophagy is strictly a parallel degradation system, or whether it is a compensatory degradation system when the UPS is impaired; furthermore, if there is a compensatory interaction between these systems, the molecular link is not known. Here we show that autophagy acts as a compensatory degradation system when the UPS is impaired in Drosophila melanogaster, and that histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase that interacts with polyubiquitinated proteins, is an essential mechanistic link in this compensatory interaction. We found that compensatory autophagy was induced in response to mutations affecting the proteasome and in response to UPS impairment in a fly model of the neurodegenerative disease spinobulbar muscular atrophy. Autophagy compensated for impaired UPS function in an HDAC6-dependent manner. Furthermore, expression of HDAC6 was sufficient to rescue degeneration associated with UPS dysfunction in vivo in an autophagy-dependent manner. This study suggests that impairment of autophagy (for example, associated with ageing or genetic variation) might predispose to neurodegeneration. Morover, these findings suggest that it may be possible to intervene in neurodegeneration by augmenting HDAC6 to enhance autophagy.     

How uncertainty can save measurement from circularity and holism

Measurement results depend upon assumptions, and some of those assumptions are theoretical in character. This paper examines particle physics measurements in which a measurement result depends upon a type of assumption for which that very same result may be evidentially relevant, thus raising a worry about potential circularity in argumentation. We demonstrate how the practice of evaluating measurement uncertainty serves to render any such evidential circularity epistemically benign. Our analysis shows how the evaluation and deployment of uncertainty evaluation constitutes an in practice solution to a particular form of Duhemian underdetermination that improves upon Duhem's vague notion of “good sense,” avoids holism, and reconciles theory dependence of measurement with piecemeal hypothesis testing.     

Constraints and divergent assessments of fertility in non-empirical physics in the history of the string theory controversy

This paper examines historic appraisals of string theory to develop a less abstract understanding of the string theory controversy and assessment in non-empirical physics. This historical approach reveals several points of conflict in the controversy, each centring on a constraint. By proceeding stepwise through these constraints, I reveal the role that constraints played in determining divergent assessments of string theory. Rather than disagreement between two competing methods, a level of agreement is found amongst those critical and supportive of string theory as to the commitment to the relevant constraints, but disagreement as to the sufficiency of consistency, the path to background independence and a non-perturbative formulation, and how to interpret the significance of applications. Furthermore, the string theory community itself is shown to be divided in its commitment to the necessity of uniqueness and the legitimacy of anthropic reasoning. These varied assessments, guided by considerations of constraints, have informed divergent claims as to the past and future fertility of string theory. These are claims as to the value of string theory in guiding research in quantum gravity: claims as to whether string theory has and will be valuable as a means rather than an end.