Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice

Kieran, Dairín; Kalmár, Bernadett; Dick, James R.; Riddoch-Contreras, Joanna; Burnstock, Geoffrey; Greensmith, Linda

doi:10.1038/nm1021

Cited by 466 publications

(381 citation statements)

References 20 publications

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“…Arimoclomol, an inducer of heat shock proteins, increased SOD1 G93A mice lifespan, delayed disease onset, improved the neuromuscular function and increased motor neuron survival, even if administered after the symptom onset (Kieran et al, 2004;Kalmar et al, 2008). The reduction of ubiquitin-positive aggregates in MNs suggests that arimoclomol presents an anti-aggregation activity in this ALS model (Kalmar et al, 2008).…”

Section: Autophagy As Therapeutic Targetmentioning

confidence: 85%

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

Mis

Brajkovic

Frattini

et al. 2016

Molecular and Cellular Neuroscience

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a b s t r a c tAutophagy is a lysosome-dependant intracellular degradation process that eliminates long-lived proteins as well as damaged organelles from the cytoplasm. An increasing body of evidence suggests that dysregulation of this system plays a pivotal role in the etiology and/or progression of neurodegenerative diseases including motor neuron disorders. Herein, we review the latest findings that highlight the involvement of autophagy in the pathogenesis of amyotrophic lateral sclerosis (ALS) and the potential role of this pathway as a target of therapeutic purposes. Autophagy promotes the removal of toxic, cytoplasmic aggregate-prone pathogenetic proteins, enhances cell survival, and modulates inflammation. The existence of several drugs targeting this pathway can facilitate the translation of basic research to clinical trials for ALS and other motor neuron diseases..

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Section: Autophagy As Therapeutic Targetmentioning

confidence: 85%

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

Mis

Brajkovic

Frattini

et al. 2016

Molecular and Cellular Neuroscience

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“…Indeed, treatment with arimoclomol, a compound that leads to increased levels of both Hsp70 and Hsp90 in the spinal cord, extended the lifespan of SOD1 G93A -transgenic mice. 14 A technical caveat has to be mentioned, because the use of fluorescent protein constructs, widely used for most cell biological FRET experiments, generally implies the possibility that the fluorescent tag alters the properties of the fused protein. For example, the EGFP tag could reduce SOD1 copper loading by precluding the interaction with its copper chaperone, or abolish the formation of physiological SOD1 dimers.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, arimoclomol treatment, known to upregulate both Hsp70 and Hsp90 in the spinal cord, extended the lifespan of SOD1 G93A -transgenic mice. 14 Alternatively, proteasomal overload and dysfunction caused by the expression of aberrantly folded SOD1 might contribute to motoneuronal demise. 15 mtSOD1 is polyubiquitinated, can be degraded by the proteasome, [16][17][18] and proteasomal activity was decreased in the lumbar spinal cord of SOD1 G93A -transgenic mice.…”

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confidence: 99%

Mutant SOD1 detoxification mechanisms in intact single cells

et al. 2007

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Mutant superoxide dismutase 1 (mtSOD1) causes dominantly inherited amyotrophic lateral sclerosis (ALS). The mechanism for mtSOD1 toxicity remains unknown. Two main hypotheses are the impairment of proteasomal function and chaperone depletion by misfolded mtSOD1. Here, we employed FRET/FLIM and biosensor imaging to quantitatively localize ubiquitination, as well as chaperone binding of mtSOD1, and to assess their effect on proteasomal and protein folding activities. We found large differences in ubiquitination and chaperone interaction levels for wild-type (wt) SOD1 versus mtSOD1 in intact single cells. Moreover, SOD1 ubiquitination levels differ between proteasomal structures and cytoplasmic material. Hsp70 binding and ubiquitination of wt and mtSOD1 species are highly correlated, demonstrating the coupled upregulation of both cellular detoxification mechanisms upon mtSOD1 expression. Biosensor imaging in single cells revealed that mtSOD1 expression alters cellular protein folding activity but not proteasomal function in the neuronal cell line examined. Our results provide the first cellby-cell-analysis of SOD1 ubiquitination and chaperone interaction. Moreover, our study opens new methodological avenues for cell biological research on ALS. Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease caused by the selective loss of motoneurons. 1 While ALS mostly occurs sporadically, 5-10% of cases are hereditary. About 20% of familial and few sporadic cases show point or frameshift mutations within the superoxide dismutase 1 (SOD1) gene. 2 The principle underlying mutant superoxide dismutase 1 (mtSOD1) toxicity seems to be a toxic gain -rather than loss -of function, since symptomatic mtSOD1-transgenic mice still express wild-type (wt), SOD1, some SOD1 mutants retain their enzymatic activity, 2,3 and neither knockout of endogenous SOD1 nor transgenic overexpression of wtSOD1 affect the course of disease in mtSOD1-transgenic mice. 4 Nonetheless, the downstream events in mtSOD1-mediated motoneuron death have not yet been resolved, although several hypotheses have been proposed that are based on properties that are specific for mtSOD1: altered protein folding, decreased solubility, and the propensity to form cytoplasmic aggregates. 5-10 One of the major hypotheses states that misfolded mtSOD1, through binding, depletes neuroprotective chaperones. 5-7 Accordingly, recombinant mtSOD1 inhibited chaperone activity in vitro. 11 Moreover, expression of Hsp70, Hsp27, or Hsp40 decreased aggregation of mtSOD1 and protected against mtSOD1 toxicity in cell lines and primary motoneurons. 6,12 However, overexpression of Hsp70 alone did not improve motoneuron survival in mtSOD1-transgenic mice. 13 This is possibly explained by a requirement, in vivo, for correction of further cellular functions or the combined action of different chaperones in the prevention of motoneuron cell death. Indeed, arimoclomol treatment, known to upregulate both Hsp70 and Hsp90 in the spinal cord, extended the lifespan of SOD1 ...

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“…Arimoclomol, a hydroxylamine derivate, amplifies Hsp expression by stabilising the binding of HSF1 to heat shock elements, leading to the upregulation of chaperones including Hsp90, Hsp70 and Hsp60. The treatment of SOD1 G93A mice with arimoclomol at pre-symptomatic or early symptomatic stages of the disease delayed disease progression, with a decrease in ubiquitin positive aggregates in the spinal cord and an improvement in muscle function and motor neuron survival at late stages of the disease [46]. This was accompanied by a 22% increase in lifespan.…”

Section: Alsmentioning

confidence: 99%

Molecular chaperones and neuronal proteostasis

Smith¹,

Li²,

Cheetham³

2015

Seminars in Cell & Developmental Biology

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Protein homeostasis (proteostasis) is essential for maintaining the functionality of the proteome. The disruption of proteostasis, due to genetic mutations or an age-related decline, leads to aberrantly folded proteins that typically lose their function. The accumulation of misfolded and aggregated protein is also cytotoxic and has been implicated in the pathogenesis of neurodegenerative diseases. Neurons have developed an intrinsic protein quality control network, of which molecular chaperones are an essential component. Molecular chaperones function to promote efficient folding and target misfolded proteins for refolding or degradation. Increasing molecular chaperone expression can suppress protein aggregation and toxicity in numerous models of neurodegenerative disease; therefore, molecular chaperones are considered exciting therapeutic targets. Furthermore, mutations in several chaperones cause inherited neurodegenerative diseases. In this review, we focus on the importance of molecular chaperones in neurodegenerative diseases, and discuss the advances in understanding their protective mechanisms.

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Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice

Cited by 466 publications

References 20 publications

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

Mutant SOD1 detoxification mechanisms in intact single cells

Molecular chaperones and neuronal proteostasis

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