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

  title={Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice},
  author={Dair{\'i}n Kieran and Bernadett Kalmar and James R. T. Dick and Joanna Riddoch-Contreras and Geoffrey Burnstock and Linda Greensmith},
  journal={Nature Medicine},
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition in which motoneurons of the spinal cord and motor cortex die, resulting in progressive paralysis. This condition has no cure and results in eventual death, usually within 1–5 years of diagnosis. Although the specific etiology of ALS is unknown, 20% of familial cases of the disease carry mutations in the gene encoding Cu/Zn superoxide dismutase-1 (SOD1). Transgenic mice overexpressing human mutant SOD1 have a phenotype… 
Heat Shock Proteins as Therapeutic Targets in Amyotrophic Lateral Sclerosis
Evidence for the involvement of the various Hsp families in disease pathology and their therapeutic potential is reviewed based on the molecular characteristics of the Hsp sub-families.
Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1G93A mouse model of ALS
Interestingly, this up‐regulation in Hsp70 was accompanied by a decrease in the number of ubiquitin‐positive aggregates in the spinal cord of treated SODG93A mice, suggesting that arimoclomol directly effects protein aggregation and degradation.
Amplifying the heat shock response ameliorates pathology in mouse and human models of ALS and FTD.
It is demonstrated that mice expressing mutant valosin containing protein (VCP) develop an ALS/FTD-like phenotype in the spinal cord and brain, and treatment with arimoclomol, a pharmacological amplifier of the cytoprotective heat shock response ameliorates this phenotype.
Exogenous Delivery of Heat Shock Protein 70 Increases Lifespan in a Mouse Model of Amyotrophic Lateral Sclerosis
The administration of recombinant human Hsp70 was effective at increasing lifespan, delaying symptom onset, preserving motor function and prolonging MN survival and results suggest rhHsp70 may delay disease progression in the G93A SOD1 mouse via a yet to be identified peripheral mechanism.
Modeling Protein Aggregation and the Heat Shock Response in ALS iPSC-Derived Motor Neurons
It is concluded that ALS iPSC-derived motor neurons recapitulate key early pathological features of the disease and fail to endogenously upregulate the HSR in response to increased protein burden.
The role of heat shock proteins in Amyotrophic Lateral Sclerosis: The therapeutic potential of Arimoclomol.
Administration of Recombinant Heat Shock Protein 70 Delays Peripheral Muscle Denervation in the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis
Earlier administration of Hsp70 was reported to arrest denervation with preserved large myelinated peripheral axons, and reduced glial activation in SOD1G93A mice, suggesting it modulates peripheral pathophysiology.
Treatment with an antibody directed against Nogo-A delays disease progression in the SOD1G93A mouse model of Amyotrophic lateral sclerosis.
Results show that treatment with anti-Nogo-A antibody significantly improves neuromuscular function in the SOD1(G93A) mouse model of ALS, at least during the earlier stages of disease and suggest that pharmacological inhibition of Nogo- A may be a disease-modifying approach in ALS.
The role of small heat shock proteins in mutant superoxide dismutase-linked familial amyotrophic lateral sclerosis.
It is shown that sHSPs decrease the amount of insoluble mutant S ODI in HEK2S3 cells, supporting reports that chaperone proteins prevent mutant SODI-inclusion formation and are beneficial in a mouse model Gf ALS.


Upregulation of HSP27 in a Transgenic Model of ALS
Immunocytochemical studies of the ventral horn of the spinal cord demonstrated HSP27 to be localized in the nucleus of neurons and glial cells in presymptomatic and early symptomatic animals, and the early nuclear localization was confirmed by Western blot analysis of spinal cord nuclear and cytoplasmic fractions.
Amyotrophic lateral sclerosis: A proposed mechanism
It is demonstrated that the entry of SOD1 into mitochondria depends on demetallation and that heat shock proteins block the uptake of the FALS-associated mutant S OD1 (G37R, G41D, or G93A), while having no effect on wild-type SOD 1.
Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis
Tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O–2 to O2 and H2O2 is reported.
High Threshold for Induction of the Stress Response in Motor Neurons Is Associated with Failure to Activate HSF1
The results indicate that the high threshold for induction of the stress response in motor neurons stems from an impaired ability to activate the main heat shock–stress sensor, HSF1.
Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.
Mutations of human Cu,Zn superoxide dismutase (SOD) are found in about 20 percent of patients with familial amyotrophic lateral sclerosis (ALS). Expression of high levels of human SOD containing a
Ubiquitin and heat shock protein expression in amyotrophic lateral sclerosis
Although ubiquitin, HSP72 and p57 are stress–induced proteins, they are expressed differently and might therefore have different significance in neuronal degeneration.
Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice
It is found that minocycline inhibits mitochondrial permeability-transition-mediated cytochrome c release, and this drug may be a novel therapy for ALS.
Motor neurone disease
  • K. Talbot
  • Medicine, Biology
    Postgraduate medical journal
  • 2002
If, as seems likely, complex inherited and environmental factors contribute to the pathogenesis of MND, future treatment may involve a combination of molecular based treatments or restoration of cellular integrity using stem cell grafts.
Mutant Cu/Zn-Superoxide Dismutase Proteins Have Altered Solubility and Interact with Heat Shock/Stress Proteins in Models of Amyotrophic Lateral Sclerosis*
It is reported that mutant S OD-1 proteins have altered solubility in cells relative to wild-type SOD-1 and can form a direct association with HSP70 and other stress proteins.