Biology subjects

Manzo, E.

Publications and source records attributed to Manzo, E..

3 recordsLinked to original sources

bioRxiv2025

A dNmnat-sensitized in vivo platform for unbiased discovery of regulators of neurodegeneration

Axon degeneration drives nervous system dysfunction in diverse neurological diseases and injuries. While key regulators of injury-induced Wallerian degeneration have been identified, approaches have largely relied on axotomy, a particularly extreme injury for a neuron. Here, we developed a forward genetic screening platform in the adult Drosophila wing that sensitizes neurons to degeneration through depletion of nicotinamide mononucleotide adenylyltransferase (dNmnat), the essential NAD+ biosynthetic enzyme. We screened 9,393 mutagenized chromosomes and recovered 59 mutations that suppress neurodegeneration induced by dNmant depletion, including the known pro-degenerative molecule dSarm, thereby validating our approach. We show loss of CG4098, the Drosophila homolog of the mammalian enzyme NUDT9, robustly preserved axons and induced widespread remodeling of NAD+-related metabolites, which provides a new link between cADP-ribose hydrolase activity and neuronal survival. We further show mutations in the transcription factor Abrupt resulted in elevated dNmnat protein levels and blocked axon degeneration, suggesting Abrupt normally tunes dNmnat levels and neuronal NAD+ homeostasis. dNmnat depletion is thus a versatile approach for unbiased discovery of axon death pathway components, each of which may provide new entry points for therapeutic strategies to preserve axons in neurodegenerative diseases.

neuroscience↗

bioRxiv2024

Adrenergic signaling gates astrocyte responsiveness to neurotransmitters and control of neuronal activity

How astrocytes regulate neuronal circuits is a fundamental, unsolved question in neurobiology. Nevertheless, few studies have explored the rules that govern when astrocytes respond to different neurotransmitters in vivo and how they affect downstream circuit modulation. Here, we report an unexpected mechanism in Drosophila by which G-protein coupled adrenergic signaling in astrocytes can control, or "gate," their ability to respond to other neurotransmitters. Further, we show that manipulating this pathway potently regulates neuronal circuit activity and animal behavior. Finally, we demonstrate that this gating mechanism is conserved in mammalian astrocytes, arguing it is an ancient feature of astrocyte circuit function. Our work establishes a new mechanism by which astrocytes dynamically respond to and modulate neuronal activity in different brain regions and in different behavioral states.

neuroscience↗

bioRxiv2019

Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS

Amyotrophic Lateral Sclerosis (ALS), is a fatal neurodegenerative disorder, with TDP-43 inclusions as a major pathological hallmark. Using a Drosophila model of TDP-43 proteinopathy we found significant alterations in glucose metabolism including increased pyruvate, suggesting that modulating glycolysis may be neuroprotective. Indeed, a high sugar diet improves locomotor and lifespan defects caused by TDP-43 proteinopathy in motor neurons or glia, but not muscle, suggesting that metabolic dysregulation occurs in the nervous system. Overexpressing human glucose transporter GLUT-3 in motor neurons mitigates TDP-43 dependent defects in synaptic vesicle recycling and improves locomotion. Furthermore, PFK mRNA, a key indicator of glycolysis, is upregulated in flies and patient derived iPSC motor neurons with TDP-43 pathology. Surprisingly, PFK overexpression rescues TDP-43 induced locomotor deficits. These findings from multiple ALS models show that mechanistically, glycolysis is upregulated in degenerating motor neurons as a compensatory mechanism and suggest that increased glucose availability is protective.

neuroscience↗