Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity

Janine Tutas  ^{1   2} , Marianna Tolve  ^{1   2} , Ebru Özer-Yildiz  ^{1   2} , Lotte Ickert  ^{1   2} , Ines Klein  ³ , Quinn Silverman  ³ , Filip Liebsch  ⁴ , Frederik Dethloff  ⁵ , Patrick Giavalisco  ⁵ , Heike Endepols  ^{6   7   8} , Theodoros Georgomanolis  ¹ , Bernd Neumaier  ^{7   8} , Alexander Drzezga  ^{7   9   10} , Guenter Schwarz  ^{4   11} , Bernard Thorens  ¹² , Graziana Gatto  ³ , Christian Frezza  ^{1   13} , Natalia L Kononenko  ^{14   15   16   17}

Affiliations

• PMID: 39815080
• PMCID: PMC11860254
• DOI: 10.1038/s42255-024-01196-4

Abstract

Dysfunctions in autophagy, a cellular mechanism for breaking down components within lysosomes, often lead to neurodegeneration. The specific mechanisms underlying neuronal vulnerability due to autophagy dysfunction remain elusive. Here we show that autophagy contributes to cerebellar Purkinje cell (PC) survival by safeguarding their glycolytic activity. Outside the conventional housekeeping role, autophagy is also involved in the ATG5-mediated regulation of glucose transporter 2 (GLUT2) levels during cerebellar maturation. Autophagy-deficient PCs exhibit GLUT2 accumulation on the plasma membrane, along with increased glucose uptake and alterations in glycolysis. We identify lysophosphatidic acid and serine as glycolytic intermediates that trigger PC death and demonstrate that the deletion of GLUT2 in ATG5-deficient mice mitigates PC neurodegeneration and rescues their ataxic gait. Taken together, this work reveals a mechanism for regulating GLUT2 levels in neurons and provides insights into the neuroprotective role of autophagy by controlling glucose homeostasis in the brain.

MCTS2 and distinct eIF2D roles in uORF-dependent translation regulation revealed by in vitro re-initiation assays

Romane Meurs  ¹ , Mara De Matos  ¹ , Adrian Bothe  ² , Nicolas Guex  ³ , Tobias Weber  ⁴ , Aurelio A Teleman  ⁴ , Nenad Ban  ² , David Gatfield  ⁵

Affiliations

• PMID: 39748120
• PMCID: PMC11790910
• DOI: 10.1038/s44318-024-00347-3

Abstract

Ribosomes scanning from the mRNA 5′ cap to the start codon may initiate at upstream open reading frames (uORFs), decreasing protein biosynthesis. Termination at a uORF can lead to re-initiation, where 40S subunits resume scanning and initiate another translation event downstream. The noncanonical translation factors MCTS1-DENR participate in re-initiation at specific uORFs, but knowledge of other trans-acting factors or uORF features influencing re-initiation is limited. Here, we establish a cell-free re-initiation assay using HeLa lysates to address this question. Comparing in vivo and in vitro re-initiation on uORF-containing reporters, we validate MCTS1-DENR-dependent re-initiation in vitro. Using this system and ribosome profiling in cells, we found that knockdown of the MCTS1-DENR homolog eIF2D causes widespread gene deregulation unrelated to uORF translation, and thus distinct to MCTS1-DENR-dependent re-initiation regulation. Additionally, we identified MCTS2, encoded by an Mcts1 retrogene, as a DENR partner promoting re-initiation in vitro, providing a plausible explanation for clinical differences associated with DENR vs. MCTS1 mutations in humans.

Keywords: DENR-MCTS1; In Vitro Translation; Re-Initiation; eIF2D; uORF.

Principles of long-range gene regulation

Sanyami Zunjarrao  ¹ , Maria Cristina Gambetta  ²

Affiliations

• PMID: 39947017
• DOI: 10.1016/j.gde.2025.102323

Free article

Abstract

Transcription from gene promoters occurs in specific spatiotemporal patterns in multicellular organisms, controlled by genomic regulatory elements. The communication between a regulatory element and a promoter requires a certain degree of physical proximity between them; hence, most gene regulation occurs locally in the genome. However, recent discoveries have revealed long-range gene regulation strategies that enhance interactions between regulatory elements and promoters by overcoming the distances between them in the linear genome. These new findings challenge the traditional view of how gene expression patterns are controlled. This review examines long-range gene regulation strategies recently reported in Drosophila and mammals, offering insights into their mechanisms and evolution.

Genetic suppression interactions are highly conserved across genetically diverse yeast isolates

Claire Paltenghi  ¹ , Jolanda van Leeuwen  ^{1   2}

Affiliations

• PMID: 40037589
• DOI: 10.1093/g3journal/jkaf047

Abstract

Genetic suppression occurs when the phenotypic defects caused by a deleterious mutation are rescued by another mutation. Suppression interactions are of particular interest for genetic diseases, as they identify ways to reduce disease severity, thereby potentially highlighting avenues for therapeutic intervention. To what extent suppression interactions are influenced by the genetic background in which they operate remains largely unknown. However, a high degree of suppression conservation would be crucial for developing therapeutic strategies that target suppressors. To gain an understanding of the effect of the genetic context on suppression, we isolated spontaneous suppressor mutations of temperature sensitive alleles of SEC17, TAO3, and GLN1 in three genetically diverse natural isolates of the budding yeast Saccharomyces cerevisiae. After identifying and validating the genomic variants responsible for suppression, we introduced the suppressors in all three genetic backgrounds, as well as in a laboratory strain, to assess their specificity. Ten out of eleven tested suppression interactions were conserved in the four yeast strains, although the extent to which a suppressor could rescue the temperature sensitive mutant varied across genetic backgrounds. These results suggest that suppression mechanisms are highly conserved across genetic contexts, a finding that is potentially reassuring for the development of therapeutics that mimic genetic suppressors.

Keywords: Saccharomyces cerevisiae; Budding yeast; Compensatory evolution; Context-dependency; Genetic interactions; Genetic suppression.

Characterization and comparison of Schizosaccharomyces pombe cdc15 temperature-sensitive mutants

Lesley A Turner  ¹ , Aleksandar Vjestica  ^{2   3} , Alaina H Willet  ¹ , Snezhana Oliferenko  ^{2   4   5} , Kathleen L Gould  ¹

Affiliations

• PMID: 40114852
• PMCID: PMC11923602
• DOI: 10.17912/micropub.biology.001515

Abstract

The F-BAR protein Cdc15 is essential for cytokinesis in the fission yeast Schizosaccharomyces pombe , playing a key scaffolding role and connecting the actomyosin-based cytokinetic ring to the plasma membrane. Here, we compared cdc15 temperature-sensitive mutants isolated in multiple genetic screens. We determined the mutations within each cdc15 mutant allele and analyzed their growth at different temperatures. Additionally, we report a new cdc15 allele that highlights the requirement for Cdc15 in the recruitment of the early secretory pathway to the cellular division site. The new mutants described here expand the toolkit for studying cytokinesis in S. pombe .

Leveraging large-scale biobank EHRs to enhance pharmacogenetics of cardiometabolic disease medications

Marie C Sadler  ^{1   2   3} , Alexander Apostolov  ³ , Caterina Cevallos  ⁴ , Chiara Auwerx  ^{1   2   3   4} , Diogo M Ribeiro  ³ , Russ B Altman  ⁵ , Zoltán Kutalik  ^{6   7   8}

Affiliations

• PMID: 40133288
• PMCID: PMC11937416
• DOI: 10.1038/s41467-025-58152-3

Abstract

Electronic health records (EHRs) coupled with large-scale biobanks offer great promises to unravel the genetic underpinnings of treatment efficacy. However, medication-induced biomarker trajectories stemming from such records remain poorly studied. Here, we extract clinical and medication prescription data from EHRs and conduct GWAS and rare variant burden tests in the UK Biobank (discovery) and the All of Us program (replication) on ten cardiometabolic drug response outcomes including lipid response to statins, HbA1c response to metformin and blood pressure response to antihypertensives (N = 932-28,880). Our discovery analyses in participants of European ancestry recover previously reported pharmacogenetic signals at genome-wide significance level (APOE, LPA and SLCO1B1) and a novel rare variant association in GIMAP5 with HbA1c response to metformin. Importantly, these associations are treatment-specific and not associated with biomarker progression in medication-naive individuals. We also found polygenic risk scores to predict drug response, though they explained less than 2% of the variance. In summary, we present an EHR-based framework to study the genetics of drug response and systematically investigated the common and rare pharmacogenetic contribution to cardiometabolic drug response phenotypes in 41,732 UK Biobank and 14,277 All of Us participants.