Dynamic regulation of molecular chaperone gene expression in polyglutamine disease

BIOPHYSICS. For the article ''A molecular mechanism for osmolyte-induced protein stability,'' by Timothy O. Street, D. Wayne Bolen, and George D. Rose, which appeared in issue 38, September 19, 2006, of Proc Natl Acad Sci USA (103:13997-14002; first published September 12, 2006; 10.1073͞pnas. 0606236103), the authors note the following: ''For Fig. 2 of our article, we inadvertently published a plot of the contact surface area rather than the accessible surface area as intended. Also, the correlation coefficient given should be 0.81, not 0.88 as in the original figure caption. All other aspects of the article remain unaffected by this correction. We regret the errors.'' The corrected figure and legend appear below. To investigate the functions of circadian neurons, we added two strategies to the standard Drosophila behavioral genetics repertoire. The first was to express a polyglutamine-expanded neurotoxic protein (MJDtr78Q; MJD, Machado-Joseph disease) in the major timeless (tim)-expressing cells of the adult brain. These Tim-MJD flies were viable, in contrast to the use of cell-death gene expression for tim neuron inactivation. Moreover, they were more arrhythmic than flies expressing other neurotoxins and had low but detectable tim mRNA levels. The second extended standard microarray technology from fly heads to dissected fly brains. By combining the two approaches, we identified a population of Tim-MJD-affected mRNAs. Some had been previously identified as sex-specific and relevant to courtship, including mRNAs localized to brain-proximal fat-body tissue and brain courtship centers. Finally, we found a decrease in the number of neurons that expressed male-specific forms of the fruitless protein in the laterodorsal region of the brain. The decrease was not a consequence of toxic protein expression within these specialized cells but a likely effect of communication with neighboring TIM-expressing neurons. The data suggest a functional interaction between adjacent circadian and mating circuits within the fly brain, as well as an interaction between circadian circuits and brain-proximal fat body. C ircadian rhythms are widespread in nature. As a consequence, many aspects of behavior, metabolism, and physiology show cyclical changes during each 24-h period. These include locomotor activity rhythms, which are intimately connected to the Ϸ75 pairs of known clock neurons within the adult Drosophila brain (e.g., ref. 1). These cells express cycling levels of clock mRNA and protein, including products of the clock genes period and timeless (per and tim; ref. 2). The circadian molecular program also runs within several peripheral (noncentral brain) tissues, including eyes, Malpighian tubules, leg sensilla, and antennae (3). Peripheral tissues contribute to other circadian outputs such as olfaction (4) and reproductive behavior (5-7).Several tools exist to eliminate or inactivate Drosophila pacemaker neurons, including agents that cause cell death, e.g., the proapoptotic genes hid and reaper (8), or those that inacti...

show abstract

“…5C). These mRNAs had been previously shown to be up-regulated by polyglutamine extended proteins in different systems (35)(36)(37).…”

Section: Clock Gene Expression Is Specifically Affected In Tim-mjd Flmentioning

confidence: 96%

Neurotoxic protein expression reveals connections between the circadian clock and mating behavior in Drosophila

Kadener¹,

Villella²,

Kula

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…A biphasic hsp expression profi le has been reported in different polyQ disease models; the heat shock response is induced by short-term polyQ protein expression and reduced upon long-term expression (Chan et al 2011 ;Chou et al 2008 ;Hands et al 2008 ;Huen and Chan 2005 ). A recent study has shown that hsp22 , hsp40 and hsp70 are induced when MJDQ84 is localized in the cytoplasm but not when it is located in the nucleus in the absence of xpo1 (Chan et al 2011 ).…”

Section: Shsps and Misfolding Protein Diseasesmentioning

confidence: 94%

Drosophila Small Heat Shock Proteins: An Update on Their Features and Functions

Morrow¹,

Tanguay²

2015

Heat Shock Proteins

View full text Add to dashboard Cite

Small heat shock proteins (sHsps) are present in varying numbers in all organisms. In Drosophila melanogaster there are 12 sHsps, which have distinctive developmental expression patterns, intracellular localizations and substrate specifi cities. Even if most of Drosophila sHsps do not have a known mammalian ortholog, they share their involvement in multiple cellular processes such as cytoskeleton modulation, apoptosis and autophagy. New data on Drosophila sHsps have arisen from high-throughput genomic and proteomic studies as well as from deletion experiments. In addition to showing the complexity of this family, these experiments suggest the involvement of sHsps in new cellular processes such as the involvement of Hsp27 in piRNA biosynthesis. The goal of this review is to summarize the new fi ndings on each Drosophila sHsp and to highlight its similarity to other sHsps as well as its distinctive features.

show abstract

“…A study in a mouse model revealed a failure of some proteostasis systems in later stages of disease but before appreciable cell death (Chou et al , 2008). At earlier stages of disease, pathogenic ATXN3 induces cellular stress pathways, resulting in increased expression of certain molecular chaperones that are known to suppress expanded ATXN3 toxicity by facilitating its folding and decreasing aggregates (Bilen and Bonini, 2007; Chai et al , 1999a; Chou et al , 2008; Huen and Chan, 2005; Warrick et al , 1999). Consistent with this, heat-shock factor 1 (HSF1) was recently shown to have an early protective role by decreasing protein aggregation in C. elegans models of MJD (Teixeira-Castro et al , 2011).…”

Section: Mutant Atxn3 and Disease Pathogenesismentioning

confidence: 99%

Toward understanding Machado–Joseph disease

Costa

Paulson

2012

Progress in Neurobiology

236

View full text Add to dashboard Cite

Machado-Joseph disease (MJD), also known as Spinocerebellar ataxia type 3 (SCA3), is the most common inherited spinocerebellar ataxia and one of many polyglutamine neurodegenerative diseases. In MJD, a CAG repeat expansion encodes an abnormally long polyglutamine (polyQ) tract in the disease protein, ATXN3. Here we review MJD, focusing primarily on the function and dysfunction of ATXN3 and on advances toward potential therapies. ATXN3 is a deubiquitinating enzyme (DUB) whose highly specialized properties suggest that it participates in ubiquitin-dependent proteostasis. By virtue of its interactions with VCP, various ubiquitin ligases and other ubiquitin-linked proteins, ATXN3 may help regulate the stability or activity of many proteins in diverse cellular pathways implicated in proteotoxic stress response, aging, and cell differentiation. Expansion of the polyQ tract in ATXN3 is thought to promote an altered conformation in the protein, leading to changes in interactions with native partners and to the formation of insoluble aggregates. The development of a wide range of cellular and animal models of MJD has been crucial to the emerging understanding of ATXN3 dysfunction upon polyQ expansion. Despite many advances, however, the principal molecular mechanisms by which mutant ATXN3 elicits neurotoxicity remain elusive. In a chronic degenerative disease like MJD, it is conceivable that mutant ATXN3 triggers multiple, interconnected pathogenic cascades that precipitate cellular dysfunction and eventual cell death. A better understanding of these complex molecular mechanisms will be important as scientists and clinicians begin to focus on developing effective therapies for this incurable, fatal disorder.

show abstract

Dynamic regulation of molecular chaperone gene expression in polyglutamine disease

Cited by 30 publications

References 52 publications

Neurotoxic protein expression reveals connections between the circadian clock and mating behavior in Drosophila

Neurotoxic protein expression reveals connections between the circadian clock and mating behavior in Drosophila

Drosophila Small Heat Shock Proteins: An Update on Their Features and Functions

Toward understanding Machado–Joseph disease

Contact Info

Product

Resources

About