DNA plasticity and damage in amyotrophic lateral sclerosis

Penndorf, Diane; Witte, Otto W.; Kretz, Alexandra

doi:10.4103/1673-5374.226377

Cited by 26 publications

(14 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another alternative mechanism might be a consequence of the role that VRK1 plays in the cellular response to DNA damage 11,12,16,37,47 . It is well known that mutations in genes coding for proteins that participate in DNA-damage responses cause neurodegerative syndromes 66,67 , such as Nijmegen 68 , Cockayne syndromes 69 and many others 67 , including amyotrophic lateral sclerosis 70 . Therefore, it is likely that alterations in DDR by a VRK1 deficiency can lead to neurodevelopmental phenotypes.…”

Section: Discussionmentioning

confidence: 99%

VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes

Martín-Doncel

Rojas

Cantarero

et al. 2019

Sci Rep

View full text Add to dashboard Cite

Very rare polymorphisms in the human VRK1 (vaccinia-related kinase 1) gene have been identified in complex neuromotor phenotypes associated to spinal muscular atrophy (SMA), pontocerebellar hypoplasia (PCH), microcephaly, amyotrophic lateral sclerosis (ALS) and distal motor neuron dysfunctions. The mechanisms by which these VRK1 variant proteins contribute to the pathogenesis of these neurological syndromes are unknown. The syndromes are manifested when both of these rare VRK1 polymorphic alleles are implicated, either in homozygosis or compound heterozygosis. In this report, to identify the common underlying pathogenic mechanism of VRK1 polymorphisms, we have studied all human VRK1 variants identified in these neurological phenotypes from a biochemical point of view by molecular modeling, protein stability and kinase activity assays. Molecular modelling predicted that VRK1 variant proteins are either unstable or have an altered kinase activity. The stability and kinase activity of VRK1 pathogenic variants detected two groups. One composed by variants with a reduced protein stability: R133C, R358X, L195V, G135R and R321C. The other group includes VRK1variants with a reduced kinase activity tested on several substrates: histones H3 and H2AX, p53, c-Jun, coilin and 53BP1, a DNA repair protein. VRK1 variants with reduced kinase activity are H119R, R133C, G135R, V236M, R321C and R358X. The common underlying effect of VRK1 pathogenic variants with reduced protein stability or kinase activity is a functional insufficiency of VRK1 in patients with neuromotor developmental syndromes. The G135 variant cause a defective formation of 53BP1 foci in response to DNA damage, and loss Cajal bodies assembled on coilin.

show abstract

Section: Discussionmentioning

confidence: 99%

VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes

Martín-Doncel

Rojas

Cantarero

et al. 2019

Sci Rep

View full text Add to dashboard Cite

show abstract

“…A wide range of cellular pathways have been implicated in ALS pathogenesis, as reviewed recently (Shin and Lee, 2013; Taylor et al, 2016; Balendra and Isaacs, 2018). These include altered RNA processing/metabolism, nucleolar dysfunction, RNA splicing transcriptional defects (Barmada, 2015; Fratta and Isaacs, 2018) and DNA damage (Konopka and Atkin, 2018; Penndorf et al, 2018). Proteostasis pathways have also been implicated, with impairments in autophagy and lysosomal function, the endoplasmic reticulum (ER), mitochondrial and the ubiquitin–proteasome systems described (Maharjan and Saxena, 2016; Ruegsegger and Saxena, 2016).…”

Section: Genetic Mutations and Risk Factors In Alsmentioning

confidence: 99%

Motor Neuron Susceptibility in ALS/FTD

et al. 2019

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of both upper and lower motor neurons (MNs) in the brain, brainstem and spinal cord. The neurodegenerative mechanisms leading to MN loss in ALS are not fully understood. Importantly, the reasons why MNs are specifically targeted in this disorder are unclear, when the proteins associated genetically or pathologically with ALS are expressed ubiquitously. Furthermore, MNs themselves are not affected equally; specific MNs subpopulations are more susceptible than others in both animal models and human patients. Corticospinal MNs and lower somatic MNs, which innervate voluntary muscles, degenerate more readily than specific subgroups of lower MNs, which remain resistant to degeneration, reflecting the clinical manifestations of ALS. In this review, we discuss the possible factors intrinsic to MNs that render them uniquely susceptible to neurodegeneration in ALS. We also speculate why some MN subpopulations are more vulnerable than others, focusing on both their molecular and physiological properties. Finally, we review the anatomical network and neuronal microenvironment as determinants of MN subtype vulnerability and hence the progression of ALS.

show abstract

“…Thus, SSBs more probably could be transformed into more genotoxic DSBs [6]. To date, genome damage and their inadequate repair have been linked to degenerating neurons in ALS patients; however, the underlying mechanisms remain unknown [8].…”

Section: Introductionmentioning

confidence: 99%

Nuclear Phospho-SOD1 Protects DNA from Oxidative Stress Damage in Amyotrophic Lateral Sclerosis

Bordoni¹,

Pansarasa²,

Dell’Orco

et al. 2019

JCM

View full text Add to dashboard Cite

We already demonstrated that in peripheral blood mononuclear cells (PBMCs) of sporadic amyotrophic lateral sclerosis (sALS) patients, superoxide dismutase 1 (SOD1) was present in an aggregated form in the cytoplasmic compartment. Here, we investigated the possible effect of soluble SOD1 decrease and its consequent aggregation. We found an increase in DNA damage in patients PBMCs characterized by a high level of aggregated SOD1, while we found no DNA damage in PBMCs with normal soluble SOD1. We found an activation of ataxia-telangiectasia-mutated (ATM)/Chk2 and ATM and Rad3-related (ATR)/Chk1 DNA damage response pathways, which lead to phosphorylation of SOD1. Moreover, data showed that phosphorylation allows SOD1 to shift from the cytoplasm to the nucleus, protecting DNA from oxidative damage. Such pathway was finally confirmed in our cellular model. Our data lead us to suppose that in a sub-group of patients this physiologic pathway is non-functional, leading to an accumulation of DNA damage that causes the death of particularly susceptible cells, like motor neurons. In conclusion, during oxidative stress SOD1 is phosphorylated by Chk2 leading to its translocation in the nuclear compartment, in which SOD1 protects DNA from oxidative damage. This pathway, inefficient in sALS patients, could represent an innovative therapeutic target.

show abstract

DNA plasticity and damage in amyotrophic lateral sclerosis

Cited by 26 publications

References 60 publications

VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes

VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes

Motor Neuron Susceptibility in ALS/FTD

Nuclear Phospho-SOD1 Protects DNA from Oxidative Stress Damage in Amyotrophic Lateral Sclerosis

Contact Info

Product

Resources

About