Protein Network Analysis Reveals a Functional Connectivity of Dysregulated Processes in ALS and SMA

Kubinski, Sabrina; Claus, Peter

doi:10.1177/26331055221087740

Cited by 4 publications

(3 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a recent study in ALS, Castro-Gomez et al found elevated TNT levels in ALS patients without TNI elevation or clinical signs of cardiac involvement, and thus proposed an extracardiac origin of TNT with TNT serving as a biomarker for lower motor neuron affection [ 135 ]. Although SMA and ALS have fundamentally different pathogenesis, they do partially share identical phenotype and pathomechanisms [ 136 ]. Changes of troponin isoform expression in muscles of SMA patients are described [ 137 ].…”

Section: Biomarkersmentioning

confidence: 99%

Biomarkers in 5q-associated spinal muscular atrophy—a narrative review

Lapp¹,

Freigang²,

Hagenacker³

et al. 2023

J Neurol

View full text Add to dashboard Cite

Abstract5q-associated spinal muscular atrophy (SMA) is a rare genetic disease caused by mutations in the SMN1 gene, resulting in a loss of functional SMN protein and consecutive degeneration of motor neurons in the ventral horn. The disease is clinically characterized by proximal paralysis and secondary skeletal muscle atrophy. New disease-modifying drugs driving SMN gene expression have been developed in the past decade and have revolutionized SMA treatment. The rise of treatment options led to a concomitant need of biomarkers for therapeutic guidance and an improved disease monitoring. Intensive efforts have been undertaken to develop suitable markers, and numerous candidate biomarkers for diagnostic, prognostic, and predictive values have been identified. The most promising markers include appliance-based measures such as electrophysiological and imaging-based indices as well as molecular markers including SMN-related proteins and markers of neurodegeneration and skeletal muscle integrity. However, none of the proposed biomarkers have been validated for the clinical routine yet. In this narrative review, we discuss the most promising candidate biomarkers for SMA and expand the discussion by addressing the largely unfolded potential of muscle integrity markers, especially in the context of upcoming muscle-targeting therapies. While the discussed candidate biomarkers hold potential as either diagnostic (e.g., SMN-related biomarkers), prognostic (e.g., markers of neurodegeneration, imaging-based markers), predictive (e.g., electrophysiological markers) or response markers (e.g., muscle integrity markers), no single measure seems to be suitable to cover all biomarker categories. Hence, a combination of different biomarkers and clinical assessments appears to be the most expedient solution at the time.

show abstract

Section: Biomarkersmentioning

confidence: 99%

Biomarkers in 5q-associated spinal muscular atrophy—a narrative review

Lapp¹,

Freigang²,

Hagenacker³

et al. 2023

J Neurol

View full text Add to dashboard Cite

show abstract

“…Together, recent findings open a new chapter in understanding the roles that R-loop mediated DNA damage and impaired DNA repair play in the pathogenesis of neurological disorders. Several studies, including the effect of ALS causing mutations on alteration of SMN function, loss of SMN containing gems in ALS patient cells, and the disruption of common protein networks in SMA and ALS have pointed to overlaps in the patho-mechanisms associated with two genetic neuromuscular disorders, ALS and SMA (Veldink et al, 2005 ; Achsel et al, 2013 ; Cauchi, 2014 ; Sun et al, 2015 ; Kubinski and Claus, 2022 ). One of the common links between different neurodegenerative disorders highlighted here is the gradual accumulation of DNA damage leading to genomic instability as one of the hallmarks of neurodegeneration.…”

Section: Mechanism Of R-loop Resolutionmentioning

confidence: 99%

R-loop Mediated DNA Damage and Impaired DNA Repair in Spinal Muscular Atrophy

Cuartas

Gangwani

2022

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Defects in DNA repair pathways are a major cause of DNA damage accumulation leading to genomic instability and neurodegeneration. Efficient DNA damage repair is critical to maintain genomicstability and support cell function and viability. DNA damage results in the activation of cell death pathways, causing neuronal death in an expanding spectrum of neurological disorders, such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Alzheimer’s disease (AD), and spinal muscular atrophy (SMA). SMA is a neurodegenerative disorder caused by mutations in the Survival Motor Neuron 1 (SMN1) gene. SMA is characterized by the degeneration of spinal cord motor neurons due to low levels of the SMN protein. The molecular mechanism of selective motor neuron degeneration in SMA was unclear for about 20 years. However, several studies have identified biochemical and molecular mechanisms that may contribute to the predominant degeneration of motor neurons in SMA, including the RhoA/ROCK, the c-Jun NH2-terminal kinase (JNK), and p53-mediated pathways, which are involved in mediating DNA damage-dependent cell death. Recent studies provided insight into selective degeneration of motor neurons, which might be caused by accumulation of R-loop-mediated DNA damage and impaired non-homologous end joining (NHEJ) DNA repair pathway leading to genomic instability. Here, we review the latest findings involving R-loop-mediated DNA damage and defects in neuron-specific DNA repair mechanisms in SMA and discuss these findings in the context of other neurodegenerative disorders linked to DNA damage.

show abstract

“…SG are observed in most tested organisms ranging from yeast to mammals, establishing their formation as an evolutionary conserved stress-induced eukaryotic response. In mammals, SG form in virtually any analysed type of cells including neurons (Aramburu-Nunez et al, 2022), muscle cells (Kubinski and Claus, 2022), and blood cells (Ghisolfi et al, 2012), or tissues such as brain (DeGracia and Hu, 2007;DeGracia et al, 2008;Degracia and Hu, 2013) and muscles (Kubinski and Claus, 2022), either promoting cell adaptation to stress required for maintaining the normal cell physiology, or contributing to the development of stress-associated diseases including neurodegenerative pathologies (Hu et al, 2022) and cancer (Aulas et al, 2020;Lee and Namkoong, 2022). Stress-inducing SG includes environmental stress such as radiation (Moeller et al, 2004;Moutaoufik et al, 2014), exposure to chemical drugs such as arsenite (Kedersha et al, 2005), pathological stress such as viral infection (Mazroui et al, 2006), or physiological stress due to oxygen- (Moeller et al, 2004;Fahling, 2009), amino acids (Damgaard and Lykke-Andersen, 2011)-, or glucosedeprivation (Buchan et al, 2011;Wang et al, 2022), and chemotherapeutic stress generated during therapy (Fournier et al, 2010;Adjibade et al, 2015;Szaflarski et al, 2016;Adjibade et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Stress granules: stress-induced cytoplasmic mRNPs compartments linked to mRNA translational regulatory pathways

Adjibade

Mazrouï

2023

Front. RNA Res.

View full text Add to dashboard Cite

Stress granules (SG) are macro-complexes that assemble as phase-separated and dynamic RNA biocondensates in the cytoplasm of the eukaryotic cell when the initiation step of the general translation of mRNAs is stalled. This occurs mainly as an adaptive cell response to either environmental (i.e., radiation, exposure to chemical drugs), pathological (i.e., viral treatment), physiological (i.e., oxygen-, amino acids-, and glucose-deprivation), or therapeutic (i.e., treatment with anti-cancer drugs) translational stress. SG also formed when translation initiation is blocked through stress-independent events including alteration of the activities of specific translation initiation factors and RNA-binding proteins. Both stress-dependent and–independent inhibition of translation initiation results in the accumulation of untranslated mRNAs, considered as integral components of SG. Consistently, in vivo assays of SG assembly combined with in vitro-based assembly of SG-like biocondensates studies support a fundamental role of the accumulation of untranslated mRNA in initiating the formation of SG, which then further promote their repression, potentially in a feed-back regulatory mechanism. The potential role of SG in actively repressing translation of associated mRNAs has been supported by a number of functional studies, establishing SG as critical regulatory sites of RNA homeostasis, in particular during stress. The view that the SG environment restricts translation of associated mRNAs was however challenged in studies showing that stress-induced translation repression can occur similarly in absence and presence of SG, leading to the emerging concept that formation of SG and translation repression are uncoupled processes. While it still a debate if mRNA recruitment to SG contributes to their translation repression, recent finding reported translation of reporter mRNAs in SG, suggesting rather an active translational role of SG. In this review, we describe the main translational signaling pathways that regulate the biology of SG, summarize current data supporting RNA as an integral functional component of SG, and then discuss evidence supporting or not the role of SG in regulating translation either negatively or positively during stress.

show abstract

Protein Network Analysis Reveals a Functional Connectivity of Dysregulated Processes in ALS and SMA

Cited by 4 publications

References 87 publications

Biomarkers in 5q-associated spinal muscular atrophy—a narrative review

Biomarkers in 5q-associated spinal muscular atrophy—a narrative review

R-loop Mediated DNA Damage and Impaired DNA Repair in Spinal Muscular Atrophy

Stress granules: stress-induced cytoplasmic mRNPs compartments linked to mRNA translational regulatory pathways

Contact Info

Product

Resources

About