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Ziff, O. J.

Publications and source records attributed to Ziff, O. J..

2 recordsLinked to original sources
bioRxiv2025

Conserved Aberrant Developmental Trajectories of Human and Mouse SBMA Motor Neurons

Spinal bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by a polyglutamine repeat expansion in the androgen receptor gene (AR). Lower motor neuron loss is a key feature of the disease, yet it remains poorly understood why these cells are affected. The transcriptional mechanisms underlying SBMA pathogenesis and how these evolve across developmental and disease stages remains incompletely defined. To elucidate the molecular mechanisms underlying motor neuron loss in SBMA, we first performed transcriptomic profiling of both induced pluripotent stem cell derived motor neurons (iPSC-MNs) generated from SBMA patients and laser-captured micro dissected motor neurons (LCM-MNs) from symptomatic AR100 SBMA mice. We compared differential gene expression between the two models to identify shared transcriptional programs. To address the temporal progression of molecular changes we conducted profiling at key stages of motor neurogenesis in the developing iPSC-MNs and at pre-symptomatic and end-stage disease in AR100 SBMA mice to elucidate the emergence of the transcriptional phenotype and the trajectory of the gene expression changes. We found significant transcriptional convergence between these two species. Notably, shared dysregulation was observed in pathways related to the spliceosome, the cell cycle and mitochondrial function. These transcriptional alterations emerged early in motor neurogenesis suggesting a developmental component to SBMA. Further in AR100 LCM-MNs we also observed disruption of mitochondrial and DNA damage repair pathways from pre-symptomatic to end stage disease. This study identifies conserved pathogenic mechanisms across two SBMA model systems and provides crucial insights into the molecular basis and temporal dynamics of SBMA progression which may help identify potential therapeutic targets for SBMA. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/674754v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1577034org.highwire.dtl.DTLVardef@187824eorg.highwire.dtl.DTLVardef@17bf6a5org.highwire.dtl.DTLVardef@17e09f9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗
bioRxiv2024

Mutations in PSEN1 predispose inflammation in an astrocyte model of familial Alzheimer's disease through disrupted regulated intramembrane proteolysis

Mutations in PSEN1 cause familial Alzheimers disease with almost complete penetrance. Age at onset is highly variable between different PSEN1 mutations and even within families with the same mutation. Current research into late onset Alzheimers disease implicates inflammation in both disease onset and progression. PSEN1 is the catalytic subunit of {gamma}-secretase, responsible for regulated intramembrane proteolysis of numerous substrates that include cytokine receptors. For this reason, we tested the hypothesis that mutations in PSEN1 impact inflammatory responses in astrocytes, thereby contributing to disease progression. Here, using iPSC-astrocytes, we show that PSEN1 is upregulated in response to inflammatory stimuli, and this upregulation is disrupted by pathological PSEN1 mutations. Using transcriptomic analyses, we demonstrate that PSEN1 mutant astrocytes have an augmented inflammatory profile in their basal state, concomitant with an upregulation of genes coding for regulated intramembrane proteolytic and robust activation of JAK-STAT signalling. Using JAK-STAT2 as an example signalling pathway, we show altered phosphorylation cascades in PSEN1 mutant astrocytes, reinforcing the notion of altered cytokine signalling cascades. Finally, we use small molecule modulators of {gamma}-secretase to confirm a role for PSEN1/{gamma}-secretase in regulating the astrocytic response to inflammatory stimuli. Together, these data suggest that mutations in PSEN1 enhance cytokine signalling via impaired regulated intramembrane proteolysis, thereby predisposing astrocytic inflammatory profiles. These findings support a two-hit contribution of PSEN1 mutations to fAD pathogenesis, not only impacting APP and A{beta} processing but also altering the cellular response to inflammation.

neuroscience↗