Biology subjects

Tomasello, D. L.

Publications and source records attributed to Tomasello, D. L..

4 recordsLinked to original sources

bioRxiv2026

IGF1 peptide targets Rett Syndrome astrocytes to degrade IGF binding protein, rescue synaptogenesis and restore mitochondrial function

Rett syndrome (RTT), a severe neurodevelopmental disorder caused by mutations in MECP2, leads to profound synaptic and circuit deficits in the brain. While neurons have historically been the focus of RTT pathology, emerging evidence implicates astrocytes in non-cell autonomous mechanisms that impair synaptic structure, function and development. Here, we uncover a central role for astrocyte-secreted IGFBP2 in mediating these deficits and demonstrate that treatment with an IGF1-derived peptide restores synapse formation by promoting IGFBP2 degradation. Using an indirect astrocyte-neuron co-culture system, we show that astrocytes derived from RTT model mice suppress excitatory synapse formation in wild-type neurons and that this impairment is reversed when RTT astrocytes are treated with IGF1(1-3) peptide. Proteomic analysis reveals elevated levels of IGFBP2 in RTT astrocytes and their conditioned media. IGF1(1-3) peptide treatment leads to proteasomal degradation of IGFBP2, increasing IGF1 bioavailability, restoring mitochondrial function, and enhancing downstream PI3K/Akt signaling in neurons. Our data define a molecular mechanism by which astrocyte dysfunction in RTT can be rescued and provide a mechanistic basis for the therapeutic efficacy of IGF1(1-3) peptide, including Trofinetide, an FDA-approved IGF1 peptide mimetic, in RTT. Significance StatementAstrocyte dysfunction is increasingly recognized as a contributor to neurodevelopmental disorders, yet their precise mechanisms of action remain elusive. Here, we identify IGFBP2 as a key astrocyte-derived inhibitor of synaptogenesis in Rett syndrome. We show that an IGF1-derived peptide, IGF1(1-3), depletes IGFBP2 via proteasomal degradation. This restores IGF1 bioavailability and rescues synaptic function in a non-cell-autonomous manner. These findings provide a mechanistic explanation for the clinical efficacy of IGF1 peptide and its mimetics in Rett syndrome, and highlight astrocytes as rational therapeutic targets in neurodevelopmental and other disorders.

neuroscience↗

bioRxiv2023

Rett Syndrome astrocytes disrupt neuronal activity and cerebral organoid development through transfer of dysfunctional mitochondria

Studies on the function of Methyl CpG binding protein 2 (MECP2) and the consequence of MECP2 deficiency and duplication have largely focused on neurons. The function of MECP2 in human glia, along with the comprehensive understanding of glial function in neurodevelopmental disorders, is much less understood. Using female and male human embryonic stem cell (hESC) lines to model MECP2 loss-of-function (LOF) in Rett Syndrome (RTT) in the developing brain, we investigated the molecular underpinnings of astrocyte (AST) development and dysfunction, and the mechanisms by which AST contribute to neuronal activity. Here we show that hESC-derived RTT ASTs have fewer mitochondria yet similar levels of reactive oxygen species compared to isogenic controls (CTR). We identified significantly diminished mitochondrial respiration that was compensated by increased glycolysis, and that the molecular mechanism behind mitochondrial dysfunction were reduced key proteins around the tricarboxylic acid (TCA) cycle and electron transport chain (ETC). We found an increased abundance of cytosolic amino acids in RTT ASTs under basal conditions that was readily depleted when energy demands were increased. We determined that RTT AST can donate their mitochondria to hESC-derived cortical neurons, and that isolated mitochondria from RTT ASTs are sufficient to cause significant changes to neuronal activity, increasing local field potentials to a hyperexcitable state. To examine mitochondrial health in the developing brain, we derived cerebral organoids. Ultrastructural analysis indicated that mitochondria from RTT hESC-derived organoids were significantly smaller compared to mitochondria from CTR organoids, indicating decreased connectivity and function, and this phenotype was stronger in glia compared to neurons. Using a multiomics epigenetics approach, we found hallmarks of RTT developmental delay and glial specific gene expression changes that corroborate altered energy metabolism and mitochondrial dysfunction. Based on these results, we propose that release of dysfunctional mitochondria from RTT ASTs to neurons furthers pathophysiology of the syndrome.

neuroscience↗

bioRxiv2023

Human iPS cell-derived sensory neurons can be infected by SARS-CoV-2 strain WA1/2020 as well as variants delta and omicron.

COVID-19 has impacted billions of people in the world since 2019 and unfolded a major healthcare crisis. With an increasing number of deaths and the emergence of more transmissible variants, it is crucial to better understand the biology of the disease-causing virus, the SARS-CoV-2. Peripheral neuropathies appeared as a specific COVID-19 symptom occurring at later stages of the disease. In order to understand the impact of SARS-CoV-2 on the peripheral nervous system, we generated human sensory neurons from induced pluripotent stem cells that we infected with the SARS-CoV-2 strain WA1/2020 and the variants delta and omicron. Using single cell RNA sequencing, we found that human sensory neurons can be infected by SARS-CoV-2 but are unable to produce new viruses. Our data suggests that sensory neurons can be infected by the original WA1/2020 strain of SARS-CoV-2 as well as the delta and omicron variants.

neuroscience↗

bioRxiv2021

FAM57B is a modulator of ceramide synthesis that regulates sphingolipid homeostasis and synaptic composition in the developing brain

The complex 16p11.2 Deletion Syndrome (16pdel) is accompanied by neurological disorders, including epilepsy, autism spectrum disorder and intellectual disability. We demonstrate that 16pdel iPSC differentiated neurons showed augmented local field potential activity and altered ceramide-related lipid species relative to unaffected. FAM57B, a poorly characterized gene in the 16p11.2 interval, has emerged as a candidate tied to symptomatology. We found that FAM57B modulates ceramide synthase (CerS) activity, but is not a CerS per se. In FAM57B mutant human neuronal cells and zebrafish brain, composition and levels of sphingolipids and glycerolipids associated with cellular membranes are disrupted. Consistently, we observed aberrant plasma membrane architecture and synaptic protein mislocalization, which were accompanied by depressed brain and behavioral activity. Together, these results suggest that haploinsufficiency of FAM57B contributes to changes in neuronal activity and function in 16pdel Syndrome, through a crucial role for the gene in lipid metabolism.

neuroscience↗