Biology subjects

Lam, R. M.

Publications and source records attributed to Lam, R. M..

3 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↗

bioRxiv2022

PIEZO2 in somatosensory neurons controls gastrointestinal transit

The gastrointestinal tract is in a state of constant motion. These movements are tightly regulated by the presence of food and help digestion by mechanically breaking down and propelling gut content. Mechanical sensing in the gut is thought to be essential for regulating motility; however, the identity of the neuronal populations, the molecules involved, and the functional consequences of this sensation are unknown. Here, we show that humans lacking PIEZO2 exhibit impaired bowel sensation and motility. Piezo2 in mouse dorsal root but not nodose ganglia is required to sense gut content, and this activity slows down food transit rates in the stomach, small intestine, and colon. Indeed, Piezo2 is directly required to detect colon distension in vivo. Our study unveils the mechanosensory mechanisms that regulate the transit of luminal contents throughout the gut, which is a critical process to ensure proper digestion, nutrient absorption, and waste removal. HighlightsO_LIIndividuals with PIEZO2 syndrome present impaired bowel sensation and gastrointestinal dysfunction. C_LIO_LIPIEZO2 in DRG neurons plays an important role in regulating gut motility. C_LIO_LILack of PIEZO2 from sensory neurons accelerates gastric emptying and intestinal transit. C_LIO_LIDRG neurons detect colon distension via PIEZO2. C_LI

neuroscience↗

bioRxiv2019

HESC-derived sensory neurons reveal an unexpected role for PIEZO2 in nociceptor mechanotransduction

Somatosensation, the detection and transduction of external and internal stimuli, has fascinated scientists for centuries. But still, some of the mechanisms how distinct stimuli are detected and transduced are not entirely understood. Over the past decade major progress has increased our understanding in areas such as mechanotransduction or sensory neuron classification. Additionally, the accessibility to human pluripotent stem cells and the possibility to generate and study human sensory neurons has enriched the somatosensory research field.\n\nBased on our previous work, the generation of functional human mechanoreceptors, we describe here the generation of hESC-derived nociceptor-like cells. We show that by varying the differentiation strategy, we can produce different nociceptive subpopulations. One protocol in particular allowed the generation of a sensory neuron population, homogeneously expressing TRPV1, a prototypical marker for nociceptors. Accordingly, we find the cells to homogenously respond to capsaicin, to become sensitized upon inflammatory stimuli, and to respond to temperature stimulation.\n\nSurprisingly, all of the generated subtypes show mechano-nociceptive characteristics and, quite unexpectedly, loss of mechanotransduction in the absence of PIEZO2.

neuroscience↗