Insights into the role of ribonuclease 4 polymorphisms in amyotrophic lateral sclerosis

Padhi, Aditya K.; Narain, Priyam; Dave, Upma; Satija, Rohit; Patir, Anirudh; Gomes, James

doi:10.1080/07391102.2017.1419147

Cited by 10 publications

(9 citation statements)

References 31 publications

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“…Loss-of-function mutations in both ANG and RNASE4 have been associated with amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) syndromes. [90][91][92][93][94][95] preferentially hydrolyzes transfer RNA (tRNA) in vivo. 96 Understanding of how tRNA-derived fragments generated by ANG may contribute to neuroprotection is rapidly expanding.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Identifies the First Risk Loci for Psychosis in Alzheimer Disease

DeMichele-Sweet

Klei

Creese

et al. 2020

Preprint

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Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD+P), affecting ~ 40% to 60% of individuals with AD. AD+P identifies a subgroup of AD patients with poor outcomes. The strongest clinical predictor of AD+P is a greater degree of cognitive impairment than in AD subjects without psychosis (AD-P). Other frequently replicated correlates of AD+P include elevated depressive symptoms. Although the estimated heritability of psychosis in AD is 61%, the underlying genetic sources of this risk are not known. We report a genome-wide meta-analysis of 12,317 AD subjects, with and without psychosis. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in the gene ENPP6 (best SNP rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p=1.26x10-8) and one spanning the 3-prime-UTR of an alternatively spliced transcript of SUMF1 (best SNP rs201109606, O.R. 0.65 (0.56-0.76), p=3.24x10-8), had genome-wide significant associations with the risk of psychosis in AD. Psychosis risk in AD demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We had previously observed a negative genetic correlation with schizophrenia, instead we now found a stronger negative correlation with the related phenotype of bipolar disorder. Psychosis risk in AD was not genetically correlated with AD or other neurodegenerative diseases. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture. Study of the genetic mechanisms underlying the associations of loci in ENPP6 and SUMF1 with psychosis in AD are warranted.

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Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Identifies the First Risk Loci for Psychosis in Alzheimer Disease

DeMichele-Sweet

Klei

Creese

et al. 2020

Preprint

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“…Since the initial discovery of SOD1 mutations in patients with ALS that account for one‐fifth of the familial cases, a number of other genetic factors have been subsequently discovered. Among them, mutations in TARDBP , FUS , VAPB , ANG , FIG4 , OPTN , VCP , SETX , and hexanucleotide repeat expansion in the C9ORF72 are primarily driven in ALS . However, as most reported cases of ALS are sporadic and known genes account for only approximately 30%‐35% of familial ALS, there is a need to study the other gene mutations thoroughly.…”

Section: Introductionmentioning

confidence: 99%

Insights into the role of d‐amino acid oxidase mutations in amyotrophic lateral sclerosis

Padhi

Hazra

2018

J of Cellular Biochemistry

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Missense mutations in the coding region of d-amino acid oxidase (DAO) have been found in patients suffering from amyotrophic lateral sclerosis (ALS). Mutations primarily impair the enzymatic activity of DAO and cause neurodegeneration due to an abnormal accumulation of d-serine in the spinal cord. However, the structural and dynamic changes that lead to impaired enzymatic activity are not fully understood. We present here extensive molecular dynamics simulations of wild-type, and all reported ALS-associated DAO mutants to elucidate the plausible mechanisms of impaired enzymatic activity, a critical function needed for neuroprotection. Simulation results show that DAO mutations disrupt several key interactions with the active site residues and decrease the conformational flexibility of active site loop comprising 216 to 228 residues, necessary for substrate binding and product release. This conformational restriction of the active site loop in the mutants is mainly due to the distortion of critical salt bridge and hydrogen bond interactions compared with wild-type. Furthermore, binding free energy calculations show that DAO mutants have a lower binding affinity toward cofactor flavin adenine dinucleotide and substrate imino-serine than the wild-type. A closer look at the cofactor and substrate interaction profiles further show that DAO mutants have lost several critical interactions with the neighboring residues as compared with wild-type. Taken together, this study provides first-hand explanation of crucial structural features that lead to the loss of enzymatic function in DAO mutants and highlights the need of further genomic scans of patients with ALS to map the association of novel DAO variants in ALS pathophysiology.

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“…In fact, the angiogenic, neurogenic and neuroprotective activities of RNase 4 have been recently demonstrated [35]. In addition, mutations in the RNase 4 gene were reported in ALS patients [36], confirming a potential use of ASC-exosomes as therapy in ALS.…”

Section: Discussionmentioning

confidence: 98%

The Anti-Apoptotic Effect of ASC-Exosomes in an In Vitro ALS Model and Their Proteomic Analysis

Bonafede

Brandi

Manfredi

et al. 2019

Cells

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Stem cell therapy represents a promising approach in the treatment of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). The beneficial effect of stem cells is exerted by paracrine mediators, as exosomes, suggesting a possible potential use of these extracellular vesicles as non-cell based therapy. We demonstrated that exosomes isolated from adipose stem cells (ASC) display a neuroprotective role in an in vitro model of ALS. Moreover, the internalization of ASC-exosomes by the cells was shown and the molecules and the mechanisms by which exosomes could exert their beneficial effect were addressed. We performed for the first time a comprehensive proteomic analysis of exosomes derived from murine ASC. We identified a total of 189 proteins and the shotgun proteomics analysis revealed that the exosomal proteins are mainly involved in cell adhesion and negative regulation of the apoptotic process. We correlated the protein content to the anti-apoptotic effect of exosomes observing a downregulation of pro-apoptotic proteins Bax and cleaved caspase-3 and upregulation of anti-apoptotic protein Bcl-2 α, in an in vitro model of ALS after cell treatment with exosomes. Overall, this study shows the neuroprotective effect of ASC-exosomes after their internalization and their global protein profile, that could be useful to understand how exosomes act, demonstrating that they can be employed as therapy in neurodegenerative diseases.

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Insights into the role of ribonuclease 4 polymorphisms in amyotrophic lateral sclerosis

Cited by 10 publications

References 31 publications

Genome-Wide Association Identifies the First Risk Loci for Psychosis in Alzheimer Disease

Genome-Wide Association Identifies the First Risk Loci for Psychosis in Alzheimer Disease

Insights into the role of d‐amino acid oxidase mutations in amyotrophic lateral sclerosis

The Anti-Apoptotic Effect of ASC-Exosomes in an In Vitro ALS Model and Their Proteomic Analysis

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