Biology subjects

Facchini, S.

Publications and source records attributed to Facchini, S..

3 recordsLinked to original sources

bioRxiv2026

White-matter disconnection shapes distributed cortical spectral dynamics after stroke

Focal brain lesions are thought to induce sleep-like slow-wave activity in perilesional cortex through altered excitation-inhibition balance and structural disconnection, but whether these dynamics extend to remote yet structurally intact regions remain unclear. Here we combined source-reconstructed high-density EEG (128 channels) with structural disconnection mapping in 49 acute stroke patients and 20 age-matched controls. Cortical regions were classified as perilesional, structurally disconnected, or non-disconnected using individual lesion masks registered to normative white-matter atlases. Perilesional cortex showed increased delta and theta power and reduced beta power relative to controls. Critically, structurally disconnected regions exhibited electrophysiological changes comparable to perilesional cortex, including enhanced low-frequency activity and steeper aperiodic spectral slopes. These alterations correlated with neurological severity and multidomain behavioral impairment. Our findings demonstrate that post-stroke slow-wave activity propagates along structural disconnection pathways, providing direct electrophysiological evidence for connectional diaschisis and identifying distributed network targets for physiology-guided neuromodulation.

neuroscience↗

bioRxiv2025

CANVAS causing AAGGG repeat expansions cause tissue-specific reduction in RFC1 expression and increase sensitivity to DNA damage

Biallelic AAGGG expansions in Replication Factor Complex Subunit 1 (RFC1) are associated with cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and are increasingly recognised as a common cause of adult-onset ataxia and sensory neuropathy. However, the disease-causing mechanisms remain unclear. Here we leveraged in vitro assays, post-mortem brain tissue, patient-derived cell lines and a neuronal Drosophila model to demonstrate that AAGGG expansions are associated with tissue-specific reductions in the expression of RFC1 transcript, along with impaired RFC1 function and increased sensitivity to DNA damage from platinum-based drugs. CRISPR/Cas9 excision of the AAGGG repeat and flanking AluSx3 element normalized RFC1 expression in iPSC-derived neurons and rescued the DNA damage response, providing a framework for future therapeutic strategies. We also show that these biological findings are clinically relevant in heterozygous AAGGG expansion carriers, who display an increased risk and severity of neuropathy with platinum-based chemotherapy.

neuroscience↗

bioRxiv2025

Bi-allelic mutations in KCTD11 cause a new form of autosomal recessive intermediate Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disorder, characterized by progressive, length-dependent degeneration of peripheral nerves, resulting in distal muscle atrophy and weakness, foot and hand deformities, and sensory deficits. The disease is clinically and genetically heterogeneous, with over 125 disease-causing genes identified to date. Here, genetic studies in ten patients from 5 unrelated families of diverse ethnic background, led to the identification of KCTD11 as a novel CMT gene, responsible for a new autosomal recessive intermediate CMT subtype, RI-CMTE. The variants identified are loss of function. KCTD11 encodes KCTD11/REN, a protein of yet unknown function in the Peripheral Nervous System, known to regulate HDAC1, {beta}-catenin, and mTORC1, key regulators of myelination and neuronal differentiation in the PNS. To explore KCTD11s role in the PNS, we used a constitutive Kctd11-/- mouse model and the derived in vitro myelin model of sensory neuron and Schwann cell co-culture (DRGN/SC), to mimic the loss-of-function induced by patient mutations. We first demonstrate that the loss of KCTD11 is due to enhanced degradation of the mutated protein via autophagy. Both in vitro and in vivo, we demonstrate abnormal myelination in vivo and altered myelination dynamics in vitro. These defects were associated with dysregulation of the expression of key transcription factors in Schwann cells, such as Egr2 and Sox10, along with other myelin-related genes, as revealed by mRNA-sequencing data. Regarding pathophysiological mechanisms, we identified dysregulation of HDAC1 expression, as well as alterations in the Wnt/{beta}-catenin, Sonic Hedgehog and Hippo/YAP signaling pathways. The deregulation of these pathways seem to converge to altered autophagy and altered balance between proliferation, differentiation and apoptosis, at least in Schwann cells. These mechanisms remain to be explored in axons from PNS neurons. Altogether, our results identify KCTD11 as a novel gene defective in autosomal recessive intermediate RI-CMTE and highlight the key role of KCTD11 in maintaining myelin homeostasis through regulation of HDAC1 and phosphorylated {beta}-catenin levels, thereby preventing late-onset myelin abnormalities and degradation.

genetics↗