Biology subjects

Andres-Benito, P.

Publications and source records attributed to Andres-Benito, P..

5 recordsLinked to original sources

bioRxiv2024

A functional interaction between TDP-43 and USP10 reveals USP10 dysfunction in TDP-43 proteinopathies

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders characterised by the progressive degeneration of specific neurons, that are defined by the appearance of TDP-43 pathology leading to TDP-43 cytoplasmic aggregation coupled with its nuclear loss. Although the causes of TDP-43 pathology in TDP-43 proteinopathies remain unclear, stress response may play a significant role, with some TDP-43 co-localizing with stress granules (SG). The ubiquitin-specific protease 10 (USP10) is a critical inhibitor of SG assembly. Here, we identify a new functional interaction between TDP-43 and USP10, with both proteins modulating different key aspects of the biology of the other. Adding to their functional connection, we assign a new function to USP10 as a modulator of alternative splicing, sharing a subset of splicing targets with TDP-43. Critically, we found that USP10 levels can increase in postmortem tissue from ALS and FTD patients and that USP10 can ameliorate TDP-43 mediated toxicity in vivo in an animal model, overall suggesting a new role for USP10 in TDP-43 proteinopathies.

neuroscience↗

bioRxiv2024

Involvement of the cellular prion protein in seeding and spreading of sarkosyl-derived fractions of Alzheimer's disease in Prnp mutant mice and in the P301S transgenic tauopathy mice model

The natural cellular prion protein is known to play several roles during development and adult brain. Far from its pathological roles in prionopathies, the non-pathogenic cellular prion protein has been described as a receptor for several amyloid in oligomeric and prefibrillar forms. For some amyloids, specific domains of the protein play a crucial role in modulating amyloids cellular uptake and seeding properties. In most studies, the functions and the role of putative amyloid receptors have been analyzed by using brain extracts derived from human neurodegenerative patients. Another strategy has been to modify the genetic dosage of the natural prion protein in genetic models of different diseases. In this study, we take advantage of both approaches to examine whether this protein plays a role in the seeding and spreading of pathogenic tau. Our results point to a role of the natural prion protein in the emergence of pathogenic tau in a mouse model overexpressing the mutation P301S of the human tau gene. In contrast, its role is minor when sarkosyl-derived brain samples of Alzheimers disease are used. In fact, our results indicate that the use of this type of sample is not adequate to determine the role of a putative receptor in tau seeding and spreading.

neuroscience↗

bioRxiv2023

miR-519a-3p, found to regulate cellular prion protein during Alzheimer's disease pathogenesis, as a biomarker of asymptomatic stages

MiRNAs induce post-transcriptional gene silencing by binding to the 3-UTR of complementary messenger RNAs and causing either degradation or inhibition of translation. The clinical relevance of miRNAs as biomarkers is growing due to their stability and detection in biofluids. In this sense, diagnosis at asymptomatic stages of Alzheimers disease (AD) remains a challenge since it can only be made at autopsy according to Braak NFT staging. Achieving the objective of detecting AD at early stages would allow possible therapies to be addressed before the onset of cognitive impairment. Many studies have determined that the expression pattern of some miRNAs is deregulated in AD patients, but to date, none has been correlated with downregulated expression of cellular prion protein (PrPC) during disease progression. That is why, by means of cross studies of miRNAs up-regulated in AD with in silico identification of potential miRNAs-binding to 3UTR of human PRNP gene, we selected miR-519a-3p for our study. Other family members of miR-519 have been shown to bind to the 3UTR region of PRNP in vitro and presumably degrade PRNP mRNA. In addition, up-regulation of some of them has been reported in various tissues from AD patients, including cerebrospinal fluid, plasma, and blood serum. In fact, miR-519d-3p is marked as a bridge regulator between mild cognitive impairment and severe AD. However, none of the studies address the prodromal stages of the disease or the expression profile of miR-519 in other neurodegenerative diseases that also may present dementia. Therefore, in this study we analyzed miR-519a-3p expression in cerebral samples of AD at different stages of evolution as well as other neurodegenerative diseases such as other tauopathies and synucleinopathies. Our results show the specific and early upregulation of miR-519a-3p starting from Braak stage I of AD, suggesting its potential use as a biomarker of preclinical stages of the disease.

neuroscience↗

bioRxiv2022

Lipidomic alterations in the cerebral cortex and white matter in sporadic Alzheimer's disease

AimsNon-targeted lipidomics analysis was conducted in post-mortem human frontal cortex area 8 (GM) and white matter of the frontal lobe centrum semi-ovale (WM) to identify lipidomes in middle-aged individuals with no neurofibrillary tangles and senile plaques, and cases at progressive stages of sporadic Alzheimers disease (sAD). MethodsLipidomic analysis using an LC-MS/MS platform was carried out in selected cases with suitable post-mortem lacking co-morbidities and concomitant brain pathologies. Complementary data were obtained using RT-qPCR and immunohistochemistry. ResultsThe WM shows an adaptive lipid phenotype resistant to lipid peroxidation, characterized by a lower fatty acid unsaturation, peroxidizability index, and higher ether lipid content than the GM. Changes in the lipidomic profile more marked in the WM than in GM occur in AD with disease progression. WM alterations are characterized by a decline in the content of branched fatty acid esters of hydroxy fatty acids (FAHFA), diacylglycerols (DG), triacylglycerols (TG), glycerophospholipids (GP) (especially ether lipids), and sphingolipids (especially sulfatides, ceramides, and glycosphingolipids). The GM acquires a fatty acid profile prone to peroxidation in sAD, while WM reinforces its peroxidation-resistant trait. Transcriptomic data point to additional defects of peroxisomal function. ConclusionsFour functional categories are associated with the different lipid classes affected in sAD: membrane structural composition, bioenergetics, antioxidant protection, and bioactive lipids, with deleterious consequences affecting both neurons and glial cells favoring disease progression.

neuroscience↗

bioRxiv2019

Nuclear lipidome is altered in amyotrophic lateral sclerosis: a preliminary study

In this pilot study, we show that nuclei in spinal cord from ALS patients exhibit a differential lipidomic signature. Among the differential lipid species we could annotate 41 potential identities. These comprise membrane-bound lipids such as phosphatidylethanolamines-including plasmalogens- and phosphatidylcholines but also other lipid classes such as glycosphingolipids, diacylglycerols, and triacylglycerides (potentially present as nuclear lipid droplets). These results were orthogonally validated by showing loss of alkyldihydroxyacetonephosphate synthase (AGPS), a key peroxisomal enzyme in plasmalogen synthesis, both in ALS necropsy samples, in human motor neurons derived from iPSC from ALS patients and in hSOD-G93A transgenic mice. Further, diacylglycerol content changes were associated to ALS-linked variations in related-enzymes, such as phospholipase C {beta}I (PLC{beta}I), the source of nuclear diacylglycerol, and protein kinase C{beta}II (PKC{beta}II), whose function partially depends on nuclei concentration of diacylglycerol. These results point out for not only a role of nuclear membrane lipids but also to lipids present in the nucleoplasm, suggesting an undisclosed role for this part of the subcellular lipidome in ALS pathophysiology.

neuroscience↗