Differences in protein quality control correlate with phenotype variability in 2 mouse models of familial amyotrophic lateral sclerosis

Marino, Marianna; Papa, Simonetta; Crippa, V.; Nardo, Giovanni; Peviani, Marco; Cheroni, Cristina; Trolese, Maria Chiara; Lauranzano, Eliana; Bonetto, Valentina; Poletti, Angelo; Debiasi, S; Ferraiuolo, Laura; Shaw, Pamela J.; Bendotti, Caterina

doi:10.1016/j.neurobiolaging.2014.06.026

Cited by 60 publications

(68 citation statements)

References 63 publications

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“…Several factors could explain why Fus ΔNLS/ + mice did not progress to the full-blown pathological and behavioral features of ALS- FUS . First, the genetic background of mice influences ALS-related disease course [31, 53]. Second, it cannot be excluded that additional hits, either environmental or genetic, are necessary for the progression of ALS- FUS , as previously postulated [18].…”

Section: Discussionmentioning

confidence: 99%

Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis

et al. 2017

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Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1687-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis

et al. 2017

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“…In cell based assays and mouse models, ALS mutant SOD1G93A and G85R show increased interaction with a number of chaperones, including Hsp70, suggesting that ALS-associated mutant species may result in a depletion of available chaperones and chaperone activity, therefore leading to cellular toxicity (Tummala et al, 2005; Ganesan et al, 2007). Furthermore, reduced levels of the chaperone alpha-B-crystallin (CRYAB) and increased incorporation of other molecular chaperones, including Hsc70, into the insoluble aggregate fraction are features of a faster progressing phenotype in SOD1G93A transgenic mice (Marino et al, 2015). …”

Section: Loss Of Protein Homeostasis In Alsmentioning

confidence: 99%

“…Furthermore, reduced expression of UPS components in the spinal cord of SOD1G93A transgenic mice has been reported (Basso et al, 2009; Marino et al, 2015), and ALS mutant SOD1 itself is poly-ubiquitinated and cleared by the proteasome (Niwa et al, 2002; Urushitani et al, 2004). Possibly, age-related reductions in UPS activity or high demand, leads to the formation of cytotoxic mutant SOD1 inclusions (Kitamura et al, 2014).…”

Section: Loss Of Protein Homeostasis In Alsmentioning

confidence: 99%

Protein Homeostasis in Amyotrophic Lateral Sclerosis: Therapeutic Opportunities?

Webster

Smith

Shaw

et al. 2017

Front. Mol. Neurosci.

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Protein homeostasis (proteostasis), the correct balance between production and degradation of proteins, is essential for the health and survival of cells. Proteostasis requires an intricate network of protein quality control pathways (the proteostasis network) that work to prevent protein aggregation and maintain proteome health throughout the lifespan of the cell. Collapse of proteostasis has been implicated in the etiology of a number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), the most common adult onset motor neuron disorder. Here, we review the evidence linking dysfunctional proteostasis to the etiology of ALS and discuss how ALS-associated insults affect the proteostasis network. Finally, we discuss the potential therapeutic benefit of proteostasis network modulation in ALS.

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“…In these patients, an anticipated onset might be linked to heavy physical exercise, repeated trauma, and/or exposure to as yet unknown toxic agents in genetically predisposed individuals (Beghi and Morrison, 2005;Pupillo et al, 2012;Beghi, 2013). A mutant SOD1 G93A mouse model of ALS on a 129Sv genetic background has an earlier age of onset than a SOD1 G93A mouse model on a C57BL6 genetic background despite an equal expression of the mutant protein (Marino et al, 2015). These mice have also faster disease progression and an intrinsic marked down-regulation of specific pathways involved in mitochondrial function and protein quality control (Nardo et al, 2013(Nardo et al, , 2016Marino et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…A mutant SOD1 G93A mouse model of ALS on a 129Sv genetic background has an earlier age of onset than a SOD1 G93A mouse model on a C57BL6 genetic background despite an equal expression of the mutant protein (Marino et al, 2015). These mice have also faster disease progression and an intrinsic marked down-regulation of specific pathways involved in mitochondrial function and protein quality control (Nardo et al, 2013(Nardo et al, , 2016Marino et al, 2015). Conversely, ApoE2 polymorphism and lower EPHA4 expression have been correlated with delayed age of onset in ALS patients (Li et al, 2004;Van Hoecke et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Decreased Levels of Foldase and Chaperone Proteins Are Associated with an Early-Onset Amyotrophic Lateral Sclerosis

Filareti

Luotti

Pasetto

et al. 2017

Front. Mol. Neurosci.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive upper and lower motor neuron degeneration. One of the peculiar clinical characteristics of ALS is the wide distribution in age of onset, which is probably caused by different combinations of intrinsic and exogenous factors. We investigated whether these modifying factors are converging into common pathogenic pathways leading either to an early or a late disease onset. This would imply the identification of phenotypic biomarkers, that can distinguish the two populations of ALS patients, and of relevant pathways to consider in a therapeutic intervention. Toward this aim a differential proteomic analysis was performed in peripheral blood mononuclear cells (PBMC) from a group of 16 ALS patients with an age of onset ≤55 years and a group of 16 ALS patients with an age of onset ≥75 years, and matched healthy controls. We identified 43 differentially expressed proteins in the two groups of patients. Gene ontology analysis revealed that there was a significant enrichment in annotations associated with protein folding and response to stress. We next validated a selected number of proteins belonging to this functional group in 85 patients and 83 age- and sex-matched healthy controls using immunoassays. The results of the validation study confirmed that there was a decreased level of peptidyl-prolyl cis-trans isomerase A (also known as cyclophilin A), heat shock protein HSP 90-alpha, 78 kDa glucose-regulated protein (also known as BiP) and protein deglycase DJ-1 in PBMC of ALS patients with an early onset. Similar results were obtained in PBMC and spinal cord from two SOD1G93A mouse models with an early and late disease onset. This study suggests that a different ability to upregulate proteins involved in proteostasis, such as foldase and chaperone proteins, may be at the basis of a different susceptibility to ALS, putting forward the development of therapeutic approaches aiming at boosting the protein quality control system.

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Differences in protein quality control correlate with phenotype variability in 2 mouse models of familial amyotrophic lateral sclerosis

Cited by 60 publications

References 63 publications

Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis

Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis

Protein Homeostasis in Amyotrophic Lateral Sclerosis: Therapeutic Opportunities?

Decreased Levels of Foldase and Chaperone Proteins Are Associated with an Early-Onset Amyotrophic Lateral Sclerosis

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