Search

Nuclear clearance and cytoplasmic accumulations of the RNA-binding protein TDP-43 are pathological hallmarks in almost all patients with amyotrophic lateral sclerosis (ALS) and up to 50% of patients with frontotemporal dementia (FTD) and Alzheimers disease. In Alzheimers disease, TDP-43 pathology is predominantly observed in the limbic system and correlates with cognitive decline and reduced hippocampal volume. Disruption of nuclear TDP-43 function leads to abnormal RNA splicing and incorporation of erroneous cryptic exons in numerous transcripts including Stathmin-2 (STMN2, also known as SCG10) and UNC13A, recently reported in tissues from patients with ALS and FTD. Here, we identify both STMN2 and UNC13A cryptic exons in Alzheimers disease patients, that correlate with TDP-43 pathology burden, but not with amyloid-β or tau deposits. We also demonstrate that processing of the STMN2 pre-mRNA is more sensitive to TDP-43 loss of function than UNC13A. In addition, full-length RNAs encoding STMN2 and UNC13A are suppressed in large RNA-seq datasets generated from Alzheimers disease post-mortem brain tissue. Collectively, these results open exciting new avenues to use STMN2 and UNC13A as potential therapeutic targets in a broad range of neurodegenerative conditions with TDP-43 proteinopathy including Alzheimers disease.

Loss of nuclear TDP-43 is a hallmark of neurodegeneration in TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 mislocalization results in cryptic splicing and polyadenylation of pre-messenger RNAs (pre-mRNAs) encoding stathmin-2 (also known as SCG10), a protein that is required for axonal regeneration. We found that TDP-43 binding to a GU-rich region sterically blocked recognition of the cryptic 3 splice site in STMN2 pre-mRNA. Targeting dCasRx or antisense oligonucleotides (ASOs) suppressed cryptic splicing, which restored axonal regeneration and stathmin-2-dependent lysosome trafficking in TDP-43-deficient human motor neurons. In mice that were gene-edited to contain human STMN2 cryptic splice-polyadenylation sequences, ASO injection into cerebral spinal fluid successfully corrected Stmn2 pre-mRNA misprocessing and restored stathmin-2 expression levels independently of TDP-43 binding.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with loss of nuclear transactive response DNA-binding protein 43 (TDP-43). Here we identify that TDP-43 regulates expression of the neuronal growth-associated factor stathmin-2. Lowered TDP-43 levels, which reduce its binding to sites within the first intron of stathmin-2 pre-messenger RNA, uncover a cryptic polyadenylation site whose utilization produces a truncated, non-functional mRNA. Reduced stathmin-2 expression is found in neurons trans-differentiated from patient fibroblasts expressing an ALS-causing TDP-43 mutation, in motor cortex and spinal motor neurons from patients with sporadic ALS and familial ALS with GGGGCC repeat expansion in the C9orf72 gene, and in induced pluripotent stem cell (iPSC)-derived motor neurons depleted of TDP-43. Remarkably, while reduction in TDP-43 is shown to inhibit axonal regeneration of iPSC-derived motor neurons, rescue of stathmin-2 expression restores axonal regenerative capacity. Thus, premature polyadenylation-mediated reduction in stathmin-2 is a hallmark of ALS-FTD that functionally links reduced nuclear TDP-43 function to enhanced neuronal vulnerability.

Through the generation of humanized FUS mice expressing full-length human FUS, we identify that when expressed at near endogenous murine FUS levels, both wild-type and ALS-causing and frontotemporal dementia (FTD)-causing mutations complement the essential function(s) of murine FUS. Replacement of murine FUS with mutant, but not wild-type, human FUS causes stress-mediated induction of chaperones, decreased expression of ion channels and transporters essential for synaptic function, and reduced synaptic activity without loss of nuclear FUS or its cytoplasmic aggregation. Most strikingly, accumulation of mutant human FUS is shown to activate an integrated stress response and to inhibit local, intra-axonal protein synthesis in hippocampal neurons and sciatic nerves. Collectively, our evidence demonstrates that human ALS/FTD-linked mutations in FUS induce a gain of toxicity that includes stress-mediated suppression in intra-axonal translation, synaptic dysfunction, and progressive age-dependent motor and cognitive disease without cytoplasmic aggregation, altered nuclear localization, or aberrant splicing of FUS-bound pre-mRNAs. VIDEO ABSTRACT.

The peroxisomal disease adrenoleukodystrophy (X-ALD) is caused by loss of the transporter of very-long-chain fatty acids (VLCFAs), ABCD1. An excess of VLCFAs disrupts essential homeostatic functions crucial for axonal maintenance, including redox metabolism, glycolysis and mitochondrial respiration. As mitochondrial function and morphology are intertwined, we set out to investigate the role of mitochondrial dynamics in X-ALD models. Using quantitative 3D transmission electron microscopy, we revealed mitochondrial fragmentation in corticospinal axons in Abcd1− mice. In patient fibroblasts, an excess of VLCFAs triggers mitochondrial fragmentation through the redox-dependent phosphorylation of DRP1 (DRP1S616). The blockade of DRP1-driven fission by the peptide P110 effectively preserved mitochondrial morphology. Furthermore, mRNA inhibition of DRP1 not only prevented mitochondrial fragmentation but also protected axonal health in a Caenorhabditis elegans model of X-ALD, underscoring DRP1 as a potential therapeutic target. Elevated levels of circulating cell-free mtDNA in patients' CSF align this leukodystrophy with primary mitochondrial disorders. Our findings underscore the intricate interplay between peroxisomal dysfunction, mitochondrial dynamics and axonal integrity in X-ALD, shedding light on potential avenues for therapeutic intervention. [ABSTRACT FROM AUTHOR]

The organisational life cycle assessment (O-LCA) and the social organisational life cycle assessment (SO-LCA) of the University of the Basque Country UPV/EHU were conducted. The data presented in this paper support the calculation of the environmental and social footprint of the University of the Basque Country UPV/EHU for year 2016 [1], and may be used as a reference for future calculations of the environmental and social footprint of higher education institutions and other organisations.This dataset provides detailed information on the UPV/EHU and the boundaries considered; on the compilation and quantification of the life cycle inventory (LCI) –which included a transport survey conducted in summer 2018–; and on the modelling process followed for the calculation of the environmental and social footprints, based on the ecoinvent 3.3 database [2] and PSILCA-based Soca v1 add-on [3, 4], and carried out with the openLCA free software [5]. The dataset also includes the life cycle impact assessment (LCIA) results provided by the CML (baseline, 2015) [6] and ReCiPe (endpoint (H), 2008) [7] LCIA methods and post-processed social impacts provided by the Social Impacts Weighting Method [3], disaggregated by subprocesses and impact locations. Data is provided for the reference year (2016), and some aggregated data is also provided for alternative scenarios that were explored in order to check pathways to reduce social and environmental impacts of the academic activity of the UPV/EHU [1].

Decreased body size is often cited as a major response to ocean warming. Available evidence, however, questions the actual emergence of shrinking trends and the prevalence of temperature‐driven changes in size over alternative drivers. In marine fish, changes in food availability or fluctuations in abundance, including those due to size‐selective fishing, provide compelling mechanisms to explain changes in body size. Here, based on three decades of scientific survey data (1990–2021), we report a decline in the average body size—length and weight—of anchovy, Engraulis encrasicolus L., in the Bay of Biscay. Shrinking was evident in all age classes, from juveniles to adults. Allometric adjustment indicated slightly more pronounced declines in weight than in total length, which is consistent with a change toward a slender body shape. Trends in adult weight were nonlinear, with rates accelerating to an average decline of up to 25% decade−1 during the last two decades. We found a strong association between higher anchovy abundance and reduced juvenile size. The effect of density dependence was less clear later in life, and temperature became the best predictor of declines in adult size. Theoretical analyses based on a strategic model further suggested that observed patterns are consistent with a simultaneous, opposing effect of rising temperatures on accelerating early growth and decreasing adult size as predicted by the temperature‐size rule. Macroecological assessment of ecogeographical—Bergmann's and James'—rules in anchovy size suggested that the observed decline largely exceeds intraspecific variation and might be the result of selection. Limitations inherent in the observational nature of the study recommend caution and a continued assessment and exploration of alternative drivers. Additional evidence of a climate‐driven regime shift in the region suggests, however, that shrinking anchovy sizes may signal a long‐lasting change in the structure and functioning of the Bay of Biscay ecosystem. [ABSTRACT FROM AUTHOR]

This paper presents the analysis, control and implementation of the interleaved three-port boost converter. The scope of this paper is the interfacing of photovoltaic systems that include storage. A new symmetrical PWM modulation strategy that prevents unwanted switching states without requiring external circuitry is presented. This modulation allows for proper sampling of the measurements, increasing thus their accuracy. Large- and small-signal models of the interleaved and non-interleaved three port boost converters are presented and transfer functions are derived for control design purposes. The different currents in the converter are controlled using control loops that govern the behavior of the converter. These loops are intuitively designed by treating them independently. With the proper loop bandwidth selection, the converter achieves fast response and good reference tracking and is suitable to interface photovoltaic and storage systems with different kinds of loads. The presented models, modulation and control loops are validated through simulation and with experimental results.