Biology subjects

Zeier, Z.

Publications and source records attributed to Zeier, Z..

4 recordsLinked to original sources

bioRxiv2025

Exercise-induced DNA damage response and memory formation in mice

This study reveals that acute aerobic exercise enhances memory formation through a controlled DNA damage mechanism, offering crucial insights into Alzheimers disease (AD) prevention. This work challenges the traditional view that DNA damage is inherently harmful, demonstrating that minor, reversible DNA single-strand breaks (SSBs) induced by exercise serve as necessary primers for memory consolidation - a mechanism that may be impaired in AD pathogenesis. AD affects 1 in 9 adults over 65, with ~95% being late-onset cases where up to 40% of risk factors are modifiable through lifestyle interventions like exercise. While exercise demonstrably lowers AD risk, underlying mechanisms remain unclear. This study provides a missing mechanistic link by showing how exercise-induced DNA damage repair systems could counteract the DNA damage accumulation and repair dysregulation that are established hallmarks of brain aging and AD. In data presented herein, young mice showed significantly higher SSB rates in active genomic regions compared to aged mice, suggesting the decline of a protective mechanism (i.e., hormesis) with aging - potentially explaining increased AD susceptibility in older adults. The present study also suggests that exercise-induced SSBs are not random cellular damage but precisely targeted events that occur at genes essential for neuroplasticity, synaptic function, and memory formation. These breaks activate PARP1 (Poly ADP ribose polymerase 1), a crucial DNA damage sensor that simultaneously initiates repair processes while facilitating transcriptional programs necessary for memory consolidation. This mechanism may represent how exercise "primes" the brain against the pathological DNA damage accumulation seen in AD. In support of this, in behavioral experiments, a single exercise bout converted sub-threshold learning into robust long-term memory formation. This memory enhancement correlated with upregulation of both neurotrophic genes (BDNF, Fos) and DNA repair enzymes (PARP1, PARP2), demonstrating coordinated damage-repair processes that appear compromised in AD. We identify HPF1 as a critical cofactor enabling PARP1 to perform trans-ADP-ribosylation of histones, linking DNA damage sensing to epigenetic chromatin remodeling required for memory-related gene expression. This pathway represents a novel therapeutic target for AD, as restoring efficient DNA repair mechanisms might slow or prevent memory loss.

neuroscience↗

bioRxiv2023

Myospreader improves gene editing in skeletal muscle by myonuclear propagation

Successful CRISPR/Cas9-based gene editing in skeletal muscle is dependent on efficient propagation of Cas9 to all myonuclei in the myofiber. However, nuclear-targeted gene therapy cargos are strongly restricted to their myonuclear domain of origin. By screening nuclear localization signals and nuclear export signals, we identify "Myospreader", a combination of short peptide sequences that promotes myonuclear propagation. Appending Myospreader to Cas9 enhances protein stability and myonuclear propagation in myoblasts and myofibers. AAV-delivered Myospreader dCas9 better inhibits transcription of toxic RNA in a myotonic dystrophy mouse model. Furthermore, Myospreader Cas9 achieves higher rates of gene editing in CRISPR reporter and Duchenne muscular dystrophy mouse models. Myospreader reveals design principles relevant to all nuclear-targeted gene therapies and highlights the importance of the spatial dimension in therapeutic development.

cell biology↗

bioRxiv2022

CRISPR/Cas9-Mediated Excision of ALS/FTD-Causing Hexanucleotide Repeat Expansion in C9ORF72 rescues major disease mechanisms in vivo and in vitro

A hexanucleotide repeat expansion (HRE) consisting of GGGGCC24+ in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both are fatal neurodegenerative diseases with no current approved treatments that significantly slow disease progression or extend life expectancy. Several hypotheses have emerged to explain how this HRE causes neuronal death, including C9ORF72 haploinsufficiency, sequestration of RNA-binding proteins in the nucleus, and production of dipeptide repeat proteins. In the present study we used a CRISPR/Cas9 gene-editing approach to remove the HRE from the C9ORF72 genomic locus, designing guide RNAs (gRNAs) flanking the HRE, and delivered Cas9 and gRNAs using adeno-associated virus serotype 9 (AAV9) vectors. Here, we demonstrate successful excision of the HRE in C9ORF72 in primary cortical neurons and brains of three mouse models containing the C9ORF72 expanded HRE (ranging from 500-600 repeats) as well as in patient-derived iPSC motor neurons and brain organoids (450 repeats). This resulted in a reduction of RNA foci, poly-dipeptides and haploinsufficiency, the major hallmarks of C9-ALS/FTD, making this an extremely attractive therapeutic approach to these diseases.

molecular biology↗

bioRxiv2020

βPix sequesters IDOL and prevents LDL receptor degradation through a β2AR-regulated signaling pathway in Alport Syndrome

Alport syndrome (AS) is a rare disease of the glomerular basement membrane type IV collagen causing progressive renal failure. We reported increased accumulation of low-density lipoprotein (LDL) receptor (LDLR) and subsequent LDL cholesterol (LDL-C) uptake in renal tubular epithelial cells (TEC) in Alport mice, but the mechanisms regulating LDLR stability and function remain unknown. Here, we show that a selective {beta}2-Adrenoceptor ({beta}2AR) agonist, salbutamol, decreased LDLR levels and LDL-C uptake in Alport kidneys accompanied with reduced albuminuria and improved cardiac systolic and diastolic function. Similarly, salbutamol decreased LDL-C uptake in HK2 and HEK293 human renal epithelial cell lines, in smooth muscle cells from an X-linked hereditary nephropathy dog model (a large animal model of AS), and in TECs differentiated from AS patient-derived iPSCs. We show that the Rac1/Cdc42 guanine nucleotide exchange factor {beta}1Pix blocked {beta}2AR-induced LDLR degradation and, hence, increased LDL-C uptake. {beta}1Pix also abrogated ubiquitination and degradation of LDLR induced by the inducible degrader of the LDLR (IDOL), an E3 ubiquitin ligase that promotes lysosomal LDLR ubiquitination and degradation. We identify a multimolecular complex comprised of {beta}Pix, IDOL, and LDLR and demonstrate that {beta}Pix counteracts {beta}2AR-mediated LDLR degradation by sequestering IDOL. Our findings show {beta}Pix acts as a significant post-transcriptional regulator of IDOL-mediated LDLR degradation and identify {beta}2AR activation as a potential treatment for Alport pathology.

molecular biology↗