Biology subjects

Caiazza, M. C.

Publications and source records attributed to Caiazza, M. C..

5 recordsLinked to original sources

bioRxiv2026

Phenotypic screening in Parkinson's iPSC-dopamine neurons identifies the FASN-SREBP1 axis as a potential therapeutic target

Parkinson's disease (PD) remains highly challenging to model in vitro, particularly when seeking robust functional phenotypes for target discovery. Patient-derived induced pluripotent stem cell dopaminergic neurons (iPSC-DANs) offer a promising platform to address this challenge. Because calcium dyshomeostasis is well-described in PD pathophysiology, it offers a platform for phenotypic screening. We have previously shown that GBA-N370S iPSC-DANs display impaired intracellular calcium release. Here, we used this disease-relevant phenotype to undertake a 4,108-compound phenotypic screen in GBA-N370S (GBA-NS) iPSC-DANs. This screen identified fatty acid synthase (FASN) as the most enriched protein target. The ability of compounds to rescue calcium release correlated with biochemical potency against FASN across multiple chemical series. We confirmed that FASN knockdown increased intracellular calcium release, supporting an on-target effect. Untargeted lipidomics demonstrated broad remodelling of the neuronal lipidome after FASN inhibition, confirming target engagement. FASN inhibition also increased active a-glucocerebrosidase (GCase), reduced extracellular a-synuclein release and ER stress, and altered RASGRF1 expression. Mechanistically, FASN inhibition activated sterol regulatory element-binding protein 1 (SREBP1), and SREBP1 overexpression alone was sufficient to increase intracellular calcium release, identifying a FASN-SREBP1-calcium homeostasis axis in human neurons. Finally, the FASN inhibitor BI 99179 achieved brain exposure and reduced brain fatty acid levels while inducing an SRE-associated transcriptional response in a Parkinson's mouse model, providing evidence of in vivo target engagement. These findings establish patient iPSC-neuron functional screening as a tractable discovery platform to identify targets which can be taken in vivo and nominate the FASN-SREBP1 axis as a candidate therapeutic pathway in PD.

neuroscience↗

bioRxiv2026

Dopamine release from Parkinson's patient-derived neurons is disrupted due to impaired synaptic vesicle loading

Striatal dopamine release defects are an early pathological feature observed in diverse models of Parkinsons disease. However, the underlying molecular mechanisms responsible, and potential links to disease aetiology in humans, have been elusive. Here, we tested the hypothesis that dopamine release deficits are a characteristic feature of disease-relevant human neurons, using human Parkinsons patient iPSC-derived dopamine neurons carrying the SNCA-triplication mutation. We reveal deficits in dopamine release from SNCA-triplication patient-derived neurons, and identify that this is due to reduced dopamine content arising from a lower capacity to store dopamine through reduced expression and function of vesicular monoamine transporter 2 (VMAT2) compared to healthy controls. In turn, by imaging VMAT substrate FFN206, and reporters for synaptic vesicular dynamics, SynaptopHluorin and CypHer5E, we reveal corresponding deficits in the size of either VMAT-containing, presynaptic releasing or recycling vesicle pools. Consistent with diminished synaptic vesicle loading and recycling, the cytosolic turnover of dopamine indicated by the ratio of concentrations of dopamine metabolite DOPAC to dopamine was elevated. By contrast, glutamate release events and VGLUT2 levels in neurons in the same preparations were not disturbed, demonstrating that vesicular dysfunction is limited to vesicles for dopamine. These findings therefore reveal dopamine loading into vesicles as a locus of dysfunction in human Parkinsons-derived neurons. These disturbances will not only drive deficits in dopamine release but could potentially also be detrimental to dopamine neuron viability through an increased burden of oxidative stress associated with elevated cytosolic dopamine, thus contributing to both symptoms and aetiology of Parkinsons pathology and offering a strategic target for improved therapies.

neuroscience↗

bioRxiv2025

TFEB and TFE3 have cell-type specific expression in the brain and divergent roles in neurons

Lysosomal dysfunction occurs in many neurodegenerative diseases, including Parkinsons disease, and activating TFEB to enhance lysosomal biogenesis is a promising therapeutic strategy. To understand TFEB physiology in cells of the brain, we characterised TFEB expression using iPSC-derived models, and transcriptomic analysis of human and mouse brain tissue. Surprisingly, TFEB expression at the RNA and protein level was restricted to glia, whereas the related transcription factor, TFE3, was expressed ubiquitously. We identified HDAC1/2/3 as transcriptional repressors of neuronal TFEB and found the brain-penetrant HDAC inhibitor ACY-738 derepressed TFEB expression and enhanced TFE3 nuclear translocation in iPSC-dopaminergic neurons (iPSC-DaNs). We delineated the role of each transcription factor by genetic manipulation in iPSC-DaNs to reveal divergent roles in which TFEB activates mitochondrial biogenesis, whereas TFE3 enhances lysosomal biogenesis. Finally, we show TFE3 activation corrects the lysosomal dysfunction associated with GBA-N370S and SNCA-Triplication mutations in Parkinsons patient-derived iPSC-DaNs, demonstrating therapeutic utility in neurodegeneration.

cell biology↗

bioRxiv2024

SARM1 activation induces reversible mitochondrial dysfunction and can be prevented in human neurons by antisense oligonucleotides

SARM1 is a key regulator of a conserved program of axon degeneration increasingly linked to human neurodegenerative diseases. Pathological SARM1 activation causes rapid NAD consumption, disrupting cellular homeostasis and leading to axon degeneration. In this study, we develop antisense oligonucleotides targeting human SARM1, demonstrating robust neuroprotection against morphological, metabolic, and mitochondrial impairment in human iPSC-derived dopamine neurons induced by the lethal neurotoxin vacor, a potent SARM1 activator. Furthermore, our findings reveal that axon fragmentation can be prevented, and mitochondrial dysfunction reversed using the NAD precursor nicotinamide, a form of vitamin B3, even after SARM1 activation has occurred, when neurons are already unhealthy. This research identifies ASOs as a promising therapeutic strategy to block SARM1, and provides an extensive characterisation and further mechanistic insights that demonstrate the reversibility of SARM1 toxicity in human neurons. It also identifies the SARM1 activator vacor as a specific and reversible neuroablative agent in human neurons.

neuroscience↗

bioRxiv2018

Nuclear Tau modulates VGluT1 expression: a new function for Tau

Summary\n\nTau displacement from microtubules is the first step in the onset of tauopathies, and is followed by toxic protein aggregation. However, other non-canonical functions of Tau might have a role in these pathologies. Here, we demonstrate that a small amount of Tau localizes in the nuclear compartment and accumulates in both the soluble and DNA-bound fractions. We show that nuclear Tau regulates the expression of VGluT1, a disease-relevant gene directly involved in glutamatergic synaptic transmission. Impeding Tau/tubulin interaction in the cytosol favours its nuclear translocation and increases VGluT1 expression. Remarkably, the P301L mutation impairs this mechanism leading to a loss of function. Altogether, our results provide the demonstration of a direct physiological role of Tau on gene expression. Alterations of this mechanism may be at the basis of the onset of neurodegeneration.

molecular biology↗