Evaluation of Neuropathological Features in the SOD1-G93A Low Copy Number Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Molnar-Kasza, Agnes; Hinteregger, Barbara; Neddens, Joerg; Rabl, Roland; Flunkert, Stefanie; Hutter‐Paier, Birgit

doi:10.3389/fnmol.2021.681868

Cited by 4 publications

(3 citation statements)

References 20 publications

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“…However, most evidence regarding microglia activation in ALS pathogenesis is related to SOD1. The SOD1 mouse model is the most used in ALS preclinical research [ 84 ]. The NF-κB is upregulated in the spinal cord of SOD1 mice, and its constitutive activation in microglia provokes gliosis and motor neuron death [ 85 ].…”

Section: Neuroinflammatory Pathways In the Genetic Als-ftd Continuummentioning

confidence: 99%

Neuroinflammatory Pathways in the ALS-FTD Continuum: A Focus on Genetic Variants

De Marchi,

Tondo,

Corrado

et al. 2023

Genes

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Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FDT) are progressive neurodegenerative disorders that, in several cases, overlap in clinical presentation, and genetic and pathological disease mechanisms. About 10–15% of ALS cases and up to 40% of FTD are familial, usually with dominant traits. ALS and FTD, in several cases, share common gene mutations, such as in C9ORF72, TARDBP, SQSTM-1, FUS, VCP, CHCHD10, and TBK-1. Also, several mechanisms are involved in ALS and FTD pathogenesis, such as protein misfolding, oxidative stress, and impaired axonal transport. In addition, neuroinflammation and neuroinflammatory cells, such as astrocytes, oligodendrocytes, microglia, and lymphocytes and, overall, the cellular microenvironment, have been proposed as pivotal players in the pathogenesis the ALS-FTD spectrum disorders. This review overviews the current evidence regarding neuroinflammatory markers in the ALS/FTD continuum, focusing on the neuroinflammatory pathways involved in the genetic cases, moving from post-mortem reports to in vivo biofluid and neuroimaging data. We further discuss the potential link between genetic and autoimmune disorders and potential therapeutic implications.

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Section: Neuroinflammatory Pathways In the Genetic Als-ftd Continuummentioning

confidence: 99%

Neuroinflammatory Pathways in the ALS-FTD Continuum: A Focus on Genetic Variants

De Marchi,

Tondo,

Corrado

et al. 2023

Genes

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“…Drug development efforts are mostly based on SOD1 gene -G93A mice that present a very strong and early phenotype, allowing only a short time window for intervention. 783 An increased expression of SIRT1 was observed in the cerebral cortex, hippocampal formation, thalamus, and spinal cord of symptomatic SOD1 (G93A) transgenic mice, but the mechanisms and functional implications of increased SIRT1 expression require elucidation. 784 In human postmortem tissue, increased mRNA and protein levels of SIRT3 were found in the spinal cord in patients with ALS.…”

Section: Introductionmentioning

confidence: 99%

The sirtuin family in health and disease

Zhang

Chen

et al. 2022

Sig Transduct Target Ther

292

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Sirtuins (SIRTs) are nicotine adenine dinucleotide(+)-dependent histone deacetylases regulating critical signaling pathways in prokaryotes and eukaryotes, and are involved in numerous biological processes. Currently, seven mammalian homologs of yeast Sir2 named SIRT1 to SIRT7 have been identified. Increasing evidence has suggested the vital roles of seven members of the SIRT family in health and disease conditions. Notably, this protein family plays a variety of important roles in cellular biology such as inflammation, metabolism, oxidative stress, and apoptosis, etc., thus, it is considered a potential therapeutic target for different kinds of pathologies including cancer, cardiovascular disease, respiratory disease, and other conditions. Moreover, identification of SIRT modulators and exploring the functions of these different modulators have prompted increased efforts to discover new small molecules, which can modify SIRT activity. Furthermore, several randomized controlled trials have indicated that different interventions might affect the expression of SIRT protein in human samples, and supplementation of SIRT modulators might have diverse impact on physiological function in different participants. In this review, we introduce the history and structure of the SIRT protein family, discuss the molecular mechanisms and biological functions of seven members of the SIRT protein family, elaborate on the regulatory roles of SIRTs in human disease, summarize SIRT inhibitors and activators, and review related clinical studies.

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“…These mice had significantly increased spinal cord holo-SOD1 and survived for an average of 540 days, whereas normal SOD1 G93A mice survived an average of 130 days, representing an almost 4-fold increase in lifespan. In addition, the disease progression could be stopped and started by addition or withdrawal of Cu-ATSM, respectively, indicating its potential use not only in the prevention of the disease but also in its treatment ( Williams et al, 2016 ; Molnar-Kasza et al, 2021 ). Conversely, simple exposure to copper without chaperones or delivery agents in vitro strongly enhances the aggregation of SOD1, so the correct chaperoning of copper is essential ( Li et al, 2013 ).…”

Section: Sod1: β-Sheets Metals and Aggregationmentioning

confidence: 99%

Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS

Min,

Sarlus,

Harris

2024

Front. Mol. Neurosci.

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The pathophysiology of ALS involves many signs of a disruption in copper homeostasis, with both excess free levels and functional deficiency likely occurring simultaneously. This is crucial, as many important physiological functions are performed by cuproenzymes. While it is unsurprising that many ALS symptoms are related to signs of copper deficiency, resulting in vascular, antioxidant system and mitochondrial oxidative respiration deficiencies, there are also signs of copper toxicity such as ROS generation and enhanced protein aggregation. We discuss how copper also plays a key role in proteostasis and interacts either directly or indirectly with many of the key aggregate-prone proteins implicated in ALS, such as TDP-43, C9ORF72, SOD1 and FUS as well as the effect of their aggregation on copper homeostasis. We suggest that loss of cuproprotein function is at the core of ALS pathology, a condition that is driven by a combination of unbound copper and ROS that can either initiate and/or accelerate protein aggregation. This could trigger a positive feedback cycle whereby protein aggregates trigger the aggregation of other proteins in a chain reaction that eventually captures elements of the proteostatic mechanisms in place to counteract them. The end result is an abundance of aggregated non-functional cuproproteins and chaperones alongside depleted intracellular copper stores, resulting in a general lack of cuproenzyme function. We then discuss the possible aetiology of ALS and illustrate how strong risk factors including environmental toxins such as BMAA and heavy metals can functionally behave to promote protein aggregation and disturb copper metabolism that likely drives this vicious cycle in sporadic ALS. From this synthesis, we propose restoration of copper balance using copper delivery agents in combination with chaperones/chaperone mimetics, perhaps in conjunction with the neuroprotective amino acid serine, as a promising strategy in the treatment of this incurable disease.

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Evaluation of Neuropathological Features in the SOD1-G93A Low Copy Number Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Cited by 4 publications

References 20 publications

Neuroinflammatory Pathways in the ALS-FTD Continuum: A Focus on Genetic Variants

Neuroinflammatory Pathways in the ALS-FTD Continuum: A Focus on Genetic Variants

The sirtuin family in health and disease

Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS

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