Biology subjects

Franchini, E.

Publications and source records attributed to Franchini, E..

4 recordsLinked to original sources

bioRxiv2026

Berberine improves motor deficits in the spastic paraplegia SPG7 mutant mice

Hereditary spastic paraplegia type 7 (SPG7) is a neurodegenerative disorder characterized by progressive motor impairment and cerebellar dysfunction. Mutations in the SPG7 gene, encoding the mitochondrial metalloprotease paraplegin, disrupt mitochondrial homeostasis and lead to neuronal vulnerability and deficits in motor coordination. Recent studies have identified defective flickering of the mitochondrial permeability transition pore (mPTP) in SPG7 models, suggesting that altered pore dynamics may represent a functional biomarker of mitochondrial dysfunction. Here, we investigated whether pharmacological modulation of mPTP activity could improve mitochondrial function and motor performance in SPG7 models. Mitochondrial flickering was assessed in vitro, while motor behavior was evaluated in vivo following chronic treatment with berberine, a natural isoquinoline alkaloid known to modulate mitochondrial bioenergetics. Spg7-/- mice and age-matched Spg7+/ littermate controls received daily oral berberine administration for several weeks, and motor coordination was assessed using the accelerating rotarod test. Untreated Spg7-/- mice exhibited reduced rotarod performance compared with controls, indicating impaired motor coordination. Berberine treatment significantly improved motor performance in pre-symptomatic mutant mice. These findings indicate that pharmacological modulation of mitochondrial permeability transition pore dynamics can ameliorate motor dysfunction associated with SPG7 deficiency and highlight mPTP flickering as a functional readout of mitochondrial health.

neuroscience↗

bioRxiv2026

Pharmacological Restoration of Mitochondrial Permeability Transition Pore Flickering by High-Content Drug Repurposing

The mitochondrial permeability transition pore (mPTP) is a voltage- and calcium-regulated channel located in the inner mitochondrial membrane whose activity critically influences cellular fate. While prolonged pore opening leads to mitochondrial depolarization, matrix swelling, and cell death, brief and reversible opening events, referred to as flickering, enable controlled release of calcium and reactive oxygen species and serve essential physiological functions. Emerging evidence indicates that restoring physiological mPTP flickering, rather than suppressing pore activity, may be beneficial in disorders characterized by impaired pore dynamics, including hereditary spastic paraplegia type 7 (SPG7). However, no approved therapies are currently available to promote controlled mPTP pore opening. To identify pharmacological modulators of flickering, we performed a high-content screening of 2,000 FDA and EMA-approved compounds using a validated fluorescence-based assay coupled with automated image analysis. Thirteen compounds increased both the frequency and the area of flickering events while preserving cellular and mitochondrial integrity. Validation in fibroblasts derived from two SPG7 patients and healthy controls confirmed reproducible activity across distinct genetic backgrounds. Among the prioritized candidates, berberine emerged as the most robust modulator, consistently enhancing mPTP flickering independently of SPG7 mutation status. Notably, berberine selectively increased the proportion of small-size flickering events, indicative of physiological pore activity. These findings identify berberine as a promising modulator of mPTP dynamics and support pharmacological restoration of physiological flickering as a potential therapeutic strategy for SPG7 and other disorders associated with impaired mitochondrial permeability transition pore regulation.

pharmacology and toxicology↗

bioRxiv2023

The ALOG domain defines a new family of plant-specific transcription factors acting during Arabidopsis flower development

The ALOGs (Arabidopsis LIGHT-DEPENDENT SHORT HYPOCOTYLS 1 and Oryza G1) are Transcription Factors (TFs) from an evolutionarily conserved plant-specific family shown to play critical roles in meristem identity, inflorescence architecture and organ boundaries in diverse species from mosses to higher flowering plants. However, the DNA binding-specificity and molecular determinants of protein-DNA interactions of this family were uncharacterized. Using in vitro genome-wide studies, we identified the conserved DNA motif bound by ALOG proteins from the liverwort Marchantia polymorpha and the flowering plants Arabidopsis, tomato and rice. In order to determine the amino acids responsible for DNA-binding specificity, we solved the 2.1[A] structure of the ALOG DNA binding domain in complex with its cognate DNA. The ALOG DBD is an all-alpha helical domain with a structural zinc ribbon insertion and an N-terminal disordered NLS. The NLS sequence forms an integral part of the DNA binding domain and contributes to direct base read-out. To define the function of a group of redundant ALOG proteins in the model plant Arabidopsis thaliana, we generated a series of alog mutants and uncovered their participation in a gene regulatory network involving the other floral regulators LEAFY, BLADE-ON-PETIOLE and PUCHI, all active in defining boundary regions between reproductive meristems and repressing bracts development. Taken together, this work provides the biochemical and structural basis for DNA-binding specificity of an evolutionarily conserved TF family and reveals its role as a key player in defining organ boundaries in Arabidopsis. Significance StatementTranscription Factors (TFs) are key proteins that bind specific regions in the genome and regulate the expression of associated genes. Not all organisms possess the same set of TFs and some, like the ALOGs, are specific to the plant kingdom. These TFs have been shown to play important roles from mosses to flowering plants. However, it was not known what DNA motif they recognize and how they bind DNA. Here we identify this motif, we show it is widely conserved in evolution and we understand how this new type of DNA binding domain works at the structural level. In addition, we also show that several ALOG genes from Arabidopsis share a redundant function within the genetic network underlying correct floral meristem development.

plant biology↗

bioRxiv2021

The ALOG family members OsG1L1 and OsG1L2 regulate inflorescence branching in rice

The architecture of the rice inflorescence is an important determinant of seed yield. The length of the inflorescence and the number of branches are among the key factors determining the amount of spikelets, and thus seeds, that will develop. Especially the timing of the identity transition from indeterminate branch meristem to determinate spikelet meristem regulates the complexity of the inflorescence. In this context, the ALOG gene TAWAWA1 (TAW1) has been shown to delay the transition to determinate spikelet development in rice. Recently, by combining precise laser microdissection of inflorescence meristems with RNA-seq we observed that two ALOG genes, Oryza sativa OsG1-like 1 (OsG1L1) and OsG1L2, have an expression profile similar to TAW1. Here we report that osg1l1 and osg1l2 loss-of-function CRISPR mutants have similar phenotypes as the taw1 mutant, suggesting that these genes might act on related pathways during inflorescence development. Transcriptome analysis of the osg1l2 mutant suggested interactions of OsG1L2 with other known inflorescence architecture regulators and the datasets were also used for the construction of a gene regulatory network (GRN) proposing interactions between genes potentially involved in controlling inflorescence development in rice. The spatio-temporal expression profiling and phenotypical analysis of CRISPR loss-of-function mutants of the homeodomain-leucine zipper transcription factor gene OsHOX14 suggest that the proposed GRN indeed serves as a valuable resource for the identification of new players involved in rice inflorescence development. One-sentence summaryOsG1L1 and OsG1L2 control panicle architecture through delaying the transition from indeterminate branch- to determinate spikelet-meristem identity.

developmental biology↗