Article

Proteasomal and autophagic degradative activities in spinal and bulbar muscular atrophy

Dipartimento di Endocrinologia, Fisiopatologia e Biologia Applicata, Università degli Studi di Milano, Milano, Italy.
Neurobiology of Disease (Impact Factor: 5.2). 11/2010; 40(2):361-9. DOI: 10.1016/j.nbd.2010.06.016
Source: PubMed

ABSTRACT Spinal and bulbar muscular atrophy (SBMA or Kennedy's disease) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons in the bulbar region of the brain and in the anterior horns of the spinal cord. The disease has been associated to an expansion of a CAG triplet repeat present in the first coding exon of the androgen receptor (AR) gene. SBMA was the first identified member of a large class of neurodegenerative diseases now known as CAG-related diseases, which includes Huntington's disease (HD), several types of spinocerebellar ataxia (SCAs), and dentatorubral and pallidoluysian atrophy (DRPLA). The expanded CAG tract is translated to an aberrantly long polyglutamine tract (ARpolyQ) in the N-terminal region of the AR protein. The elongated polyQ tract seems to confer a neurotoxic gain-of-function to the mutant AR, possibly via the generation of aberrant conformations (misfolding). Protein misfolding is thought to be a trigger of neurotoxicity, since it perturbs a wide variety of motor neuronal functions. The first event is the accumulation of the ARpolyQ into ubiquitinated aggregates in a ligand (testosterone) dependent manner. The mutant ARpolyQ also impairs proteasome functions. The autophagic pathway may be activated to compensate these aberrant events by clearing the mutant ARpolyQ from motor neuronal cells. This review illustrates the mechanisms at the basis of ARpolyQ degradation via the proteasomal and autophagic systems.

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    • "These systems work together protecting cells particularly sensitive to misfolded protein toxicity, such as motoneurons (Rusmini et al., 2010; Bendotti et al., 2012; Carra et al., 2013). Motoneurons are major targets of toxicity in diseases linked to mutant proteins prone to misfold, such as in amyotrophic lateral sclerosis (ALS) (Pasinelli and Brown, 2006; Rusmini et al., 2010; Sau et al., 2011; Strong and Yang, 2011; Carra et al., 2012, 2013; Robberecht and Philips, 2013). Most ALS cases appear in sporadic (sALS) forms; only about 10–15% have familial (fALS) history, and are clinically indistinguishable from sALS. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a motoneuron disease characterized by misfolded proteins aggregation in affected motoneurons. In mutant SOD1 (mutSOD1) ALS models, aggregation correlates to impaired functions of proteasome and/or autophagy, both essential for the intracellular chaperone-mediated protein quality control (PQC), and a reduced mutSOD1 clearance from motoneurons. Skeletal muscle cells are also sensitive to mutSOD1 toxicity, but no mutSOD1 aggregates are formed in these cells, that might better manage mutSOD1 than motoneurons. Thus, we analysed in spinal cord and in muscle of transgenic (tg) G93A-SOD1 at presymptomatic (PS, 8 weeks) and symptomatic (S, 16 weeks) stages, and in age-matched control mice, whether mutSOD1 differentially modulates relevant PQC players, such as HSPB8, BAG3, and BAG1. Possible sex differences were also considered. No changes of HSPB8, BAG3 and BAG1 at PS stage (8 weeks) were seen in all tissues examined in tg G93A-SOD1 and control mice. At S stage (16 weeks), HSPB8 dramatically increased in skeletal muscle of tg G93A-SOD1 mice, while a minor increase occurred in spinal cord of male, but not female tg G93A-SOD1 mice. BAG3 expression increased both in muscle and spinal cord of tg G93A-SOD1 mice at S stage, BAG1 expression increased only in muscle of the same mice. Since, HSPB8-BAG3 complex assists mutSOD1 autophagic removal, we analysed two well-known autophagic markers, LC3 and p62. Both LC3 and p62 mRNAs were significantly up-regulated in skeletal muscle of tg G93A-SOD1 mice at S stage (16 weeks). This suggests that mutSOD1 expression induces a robust autophagic response specifically in muscle. Together these results demonstrate that, in muscle mutSOD1-induced autophagic response is much higher than in spinal cords. In addition, if mutSOD1 exerts toxicity in muscle, this may not be mediated by misfolded protein accumulation. It remains unclear whether in muscle mutSOD1 toxicity is related to aberrant autophagy activation.
    Frontiers in Cellular Neuroscience 11/2013; 7:234. DOI:10.3389/fncel.2013.00234 · 4.18 Impact Factor
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    • "Notably, we found an inverse stabilization of ARpolyQ after testosterone treatment with or without UPS inhibition. Indeed, as shown in WB analysis, with unblocked UPS, testosterone increased ARpolyQ levels (Piccioni et al., 2002; Rusmini et al., 2007, 2010, 2011; Simeoni et al., 2000). When the UPS is inhibited, untreated ARpolyQ accumulated at very high levels, confirming its preferential degradation via UPS. "
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    ABSTRACT: Spinal and bulbar muscular atrophy (SBMA) is an X-linked motoneuron disease caused by an abnormal expansion of a tandem CAG repeat in exon 1 of the androgen receptor (AR) gene that results in an abnormally long polyglutamine tract (polyQ) in the AR protein. As a result, the mutant AR (ARpolyQ) misfolds, forming cytoplasmic and nuclear aggregates in the affected neurons. Neurotoxicity only appears to be associated with the formation of nuclear aggregates. Thus, improved ARpolyQ cytoplasmic clearance, which indirectly decreases ARpolyQ nuclear accumulation, has beneficial effects on affected motoneurons. In addition, increased ARpolyQ clearance contributes to maintenance of motoneuron proteostasis and viability, preventing the blockage of the proteasome and autophagy pathways that might play a role in the neuropathy in SBMA. The expression of heat shock protein B8 (HspB8), a member of the small heat shock protein family, is highly induced in surviving motoneurons of patients affected by motoneuron diseases, where it seems to participate in the stress response aimed at cell protection. We report here that HspB8 facilitates the autophagic removal of misfolded aggregating species of ARpolyQ. In addition, though HspB8 does not influence p62 and LC3 (two key autophagic molecules) expression, it does prevent p62 bodies formation, and restores the normal autophagic flux in these cells. Interestingly, trehalose, a well-known autophagy stimulator, induces HspB8 expression, suggesting that HspB8 might act as one of the molecular mediators of the proautophagic activity of trehalose. Collectively, these data support the hypothesis that treatments aimed at restoring a normal autophagic flux that result in the more efficient clearance of mutant ARpolyQ might produce beneficial effects in SBMA patients.
    Neurobiology of aging 06/2013; 34(11). DOI:10.1016/j.neurobiolaging.2013.05.026 · 4.85 Impact Factor
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    • "One of the characteristic features of the neurodegenerative polyglutamine diseases is the presence of inclusion bodies that colocalize with components of the UPS and the molecular chaperone pathway (Adachi et al., 2001), indicating that the mutant proteins are targeted for degradation (Stenoien et al., 1999). Potentially , sequestration of UPS components or inhibition of the UPS by polyQ proteins could alter protein repair and degradation pathways and thus have been implicated in the pathogenesis of polyglutamine diseases (Bailey et al., 2002; Rusmini et al., 2010). Degradation of an unstable green fluorescent protein reporter (GFP u ) decreased when HEK293-GFP u cells expressing the polyQ AR were treated with androgens, suggesting that proteasome activity was inhibited by the polyQ AR (Mandrusiak et al., 2003). "
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    ABSTRACT: Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease), a late-onset neuromuscular disorder, is caused by expansion of the polymorphic polyglutamine tract in the androgen receptor (AR). The AR is a ligand-activated transcription factor, but plays roles in other cellular pathways. In SBMA, selective motor neuron degeneration occurs in the brainstem and spinal cord, thus the causes of neuronal dysfunction have been studied. However, pathogenic pathways in muscles may also be involved. Cultured cells, fly and mouse models are used to study the molecular mechanisms leading to SBMA. Both the structure of the polyglutamine-expanded AR (polyQ AR) and its interactions with other proteins are altered relative to the normal AR. The ligand-dependent translocation of the polyQ AR to the nucleus appears to be critical, as are interdomain interactions. The polyQ AR, or fragments thereof, can form nuclear inclusions, but their pathogenic or protective nature is unclear. Other data suggests soluble polyQ AR oligomers can be harmful. Post-translational modifications such as phosphorylation, acetylation, and ubiquitination influence AR function and modulate the deleterious effects of the polyQ AR. Transcriptional dysregulation is highly likely to be a factor in SBMA; deregulation of non-genomic AR signaling may also be involved. Studies on polyQ AR-protein degradation suggest inhibition of the ubiquitin proteasome system and changes to autophagic pathways may be relevant. Mitochondrial function and axonal transport may also be affected by the polyQ AR. Androgens, acting through the AR, can be neurotrophic and are important in muscle development; hence both loss of normal AR functions and gain of novel harmful functions by the polyQ AR can contribute to neurodegeneration and muscular atrophy. Thus investigations into polyQ AR function have shown that multiple complex mechanisms lead to the initiation and progression of SBMA.
    Frontiers in Neurology 05/2013; 4:53. DOI:10.3389/fneur.2013.00053
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