Biology subjects

Kaluski, S.

Publications and source records attributed to Kaluski, S..

3 recordsLinked to original sources

bioRxiv2026

Aging in Fast-Forward: An Inducible SIRT6 Deficiency model as a Lens on Brain Aging and Neurodegeneration

Aging and neurodegeneration occur gradually, making in vitro modeling challenging and costly. We generated a time-resolved, reversible neuron-like aging model by gradually depleting SIRT6. Within three weeks, their transcriptomes recapitulated brain-aging signatures and hallmarks. RNA-seq revealed clusters of nonlinear changes and predicted oscillatory DNA-damage and apoptotic programs, allowing stress response and adaptation. SIRT6 loss led to nuclear envelope breakdown and micronuclei accumulation, resembling accelerated-aging phenotypes. Some defects could be rescued by re-expressing SIRT6. As a tool for discovery, we uncovered disrupted nucleocytoplasmic transport as an aging pathway shared with neurodegenerative disorders. When SIRT6 depletion reached 30 days, transcriptional changes correlated with those in Alzheimers patients, but reversed after SIRT6 re-expression. Pathways associated with shSIRT6 and healthy aging became anticorrelated with AD, pointing to critical signatures. Our affordable and easy-to-use model captures key molecular features of aging, distinguishes physiological from disease-linked changes, and accelerates mechanistic discovery in a controllable, neuron-based system. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/705977v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@181c9d1org.highwire.dtl.DTLVardef@1e8be3dorg.highwire.dtl.DTLVardef@121d345org.highwire.dtl.DTLVardef@1b5589e_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO A Novel Reversible Cellular Model of Gradual SIRT6 Decline Reveals Transcriptomic Transitions from Aging to Neurodegeneration. (1) We developed a neuron-like cellular system with gradual, inducible SIRT6 depletion to mimic the aging process. The model enables: (2) Recapitulation of hallmark features of aging, including genomic instability, cellular stress, and nuclear integrity loss. (3) Identification of novel SIRT6-regulated pathways, including impaired nucleocytoplasmic transport. (4) Clustering of dynamic, non-linear gene expression trajectories. (5) Distinction between reversible and irreversible changes following SIRT6 re-expression. (6) Transcriptomic comparison with human brain aging and AD revealing divergence points between healthy and pathological aging. C_FIG

molecular biology↗

bioRxiv2020

Molecular Mechanism of Nuclear Tau Accumulation and its Role in Protein Synthesis.

Several neurodegenerative diseases present Tau accumulation as the main pathological marker. Tau post-translational modifications such as phosphorylation and acetylation are increased in neurodegenerative patients. Here, we show that Tau hyper-acetylation at residue 174 increases its own nuclear presence and is the result of DNA damage signaling or the lack of SIRT6, both causative of neurodegeneration. Tau-K174ac is deacetylated in the nucleus by SIRT6. However, lack of SIRT6 or chronic DNA damage result in nuclear Tau-K174ac accumulation. Once there, it induces global changes in gene expression affecting protein translation, synthesis and energy production. Tau-K174Q expressing cells showed changes in the nucleolus increasing their intensity and number, as well as in rRNA synthesis leading to an increase in protein translation and ATP reduction. Concomitantly, AD patients showed increased Nucleolin and a decrease in SIRT6 levels. AD patients present increased levels of nuclear Tau, particularly Tau-K174ac. Our results suggest that increased Tau-K174ac in AD patients is the result of DNA damage signaling and SIRT6 depletion. We propose that Tau-K174ac toxicity is due to its increased stability, nuclear accumulation and nucleolar dysfunction.

molecular biology↗

bioRxiv2019

SIRT6 is a DNA double-strand break sensor

DNA double strand breaks are the most deleterious type of DNA damage. In this work, we show that SIRT6 directly recognizes DNA damage through a tunnel-like structure, with high affinity for double strand breaks. It relocates to sites of damage independently of signalling and known sensors and activates downstream signalling cascades for double strand break repair by triggering ATM recruitment, H2AX phosphorylation and the recruitment of proteins of the Homologous Recombination and Non-Homologous End Joining pathways. Our findings indicate that SIRT6 plays a previously uncharacterized role as DNA damage sensor, which is critical for initiating the DNA damage response (DDR). Moreover, other Sirtuins share some DSB binding capacity and DDR activation. SIRT6 activates the DDR, before the repair pathway is chosen, and prevents genomic instability. Our findings place SIRT6 at the top of the DDR and pave the road to dissect the contributions of distinct double strand break sensors in downstream signalling.

biochemistry↗