Biology subjects

Franco, M. C.

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

3 recordsLinked to original sources

bioRxiv2025

The structure, redox chemistry and motor neuron toxicity of heterodimeric zinc-deficient SOD1-Implications for the toxic gain of function observed in ALS.

A subset of familial cases of amyotrophic lateral sclerosis (fALS) are caused by mutations to copper, zinc superoxide dismutase (Cu, Zn SOD1). There are over 200 mutations to SOD1 that have been associated with fALS and the majority of these mutations are dominantly inherited. Thus, individuals are heterozygous and express both wild-type SOD1 and the mutant form of the protein. Paradoxically, when rodent models are produced that mimic the co-expression of wild-type SOD1 with mutant fALS SOD1 the motor neuron disease accelerates. Previously, we have shown that the loss of zinc from an SOD1 kills cultured motor neurons due to a gained, redox activity catalyzed by the active-site copper. Furthermore, motor neuron toxicity of zinc-deficient SOD1 is enhanced by wild-type Cu, Zn SOD1. Because SOD1 exists as a non-covalent dimer, the enhanced toxicity might result from stabilization of the heterodimeric interface between zinc-deficient SOD1 and Cu, Zn-SOD1. However, experimentation with the heterodimer is difficult because SOD1 subunits exchange in minutes. To better characterize the role of dimer stabilization on the enhanced toxicity of fALS mutant SOD1 by wild type SOD1, we genetically tethered a zinc-deficient SOD1 subunit with a Cu, Zn SOD1 subunit with a 16-residue linker. The x-ray structure of the tethered heterodimer shows that zinc-deficient subunit adopts a wild-type-like conformation and is not misfolded. The heterodimer intermediate also produced peroxynitrite from nitric oxide, and the tethered SOD1 was strikingly toxic to primary cultures of motor neurons. This work supports the concept that zinc-deficient SOD1 is a likely toxic intermediate in ALS. Furthermore, the wild-type allele in human familial-SOD1 ALS patients may physically contribute to the dominant inheritance of SOD1 mutations through heterodimer formation.

biochemistry↗

bioRxiv2024

Covert muscle activity reveals dynamic freezing states and prepares the animal for action

When an animal detects a threat it must make a split-second choice between fight, flight or freezing (1-3). During freezing, skeletal muscles sustain tension to maintain rigid, sometimes atypical postures, for many minutes at a time (4). Meanwhile the animal must dynamically assess its surroundings to plan future actions and ready its body for movement. The interplay between the neural and somatic systems during freezing remains poorly understood. Here we show that freezing Drosophila melanogaster display a striking novel pattern of leg muscle activation unique to immobility, a rhythmic pulsing in the distal tibia. The muscle, which we show to be a previously undescribed leg accessory heart, displays multiple activity modes and ramps up to movement onset, implying a preparation for movement. The frequency of pulsing is dynamically modulated as the fly integrates external threat or safety cues, and artificially increasing pulse frequency leads to freezing breaks, indicating a causal role in the decision to move. Through the identification of a new Drosophila cardiac organ, this study provides a window into the multiple states which can underlie freezing behaviour, and the physiological changes which the body undergoes to ready the animal to move.

neuroscience↗

bioRxiv2021

Leishmania amazonensis sabotages host cell SUMOylation for intracellular survival

Leishmania parasites use elaborate virulence mechanisms to invade and thrive in macrophages. These virulence mechanisms inhibit host cell defense responses and generate a specialized replicative niche, the parasitophorous vacuole. In this work, we performed a genome-wide RNAi screen in Drosophila macrophage-like cells to identify host factors necessary for Leishmania amazonensis infection. This screen identified 52 conserved genes required specifically for parasite entry, including several components of the SUMOylation machinery. Further studies in mammalian macrophages found that L. amazonensis infection inhibited SUMOylation within infected macrophages and this inhibition enhanced parasitophorous vacuole growth and parasite proliferation through modulation of multiple genes especially ATP6V0D2, which in turn effects CD36 expression and cholesterol levels. Together, these data suggest that parasites actively sabotage host SUMOylation and alter host transcription to improve their intracellular niche and enhance their replication.

cell biology↗