Dear all,

We are pleased to welcome Sandrine HUMBERT from the Paris Brain Institute ICM, invited by Pascale BOMONT.
She will give a seminar on May 6th  at 11:00 a.m. entitled: “Developmental origins of late-onset neurological diseases”

The seminar will take place in Amphi Hermann (1st floor) in Faculté de Médecine Lyon-Est Rockefeller.

Dr Humbert leads a team at the Paris Brain Institute, ICM. Trained as a biotech engineer, Sandrine Humbert worked during her PhD on transcription factors (JM Egly, IGBMC, Strasbourg). She then completed two post-doctoral stays (LH Tsai, Harvard Medical School, Boston and F Saudou, Institute Curie, Orsay) during which she focused on brain development and neurodegenerative processes. Since 2009, her team has combined cellular approaches with the analysis of mouse models to understand the physiological functions of huntingtin, the protein associated with Huntington disease (HD), and to characterize the mechanisms underlying HD pathogenesis. Over the past ten years, her team’s most significant contribution to the field has been to demonstrate that the developing HD brain is affected and to describe how this contributes to the pathology.

Abstract

Alzheimer disease, Parkinson disease, and Huntington disease (HD), present their full-blown forms typically after mid-adulthood. Most research on these conditions has sought to unravel the causes of the motor and cognitive deterioration and pathologies such as the clumps of misfolded proteins that figure in post-mortem samples, even though these are relatively late-stage phenomena. The dominant paradigm is that it takes time for misfolded proteins to overwhelm the cellular degradation machinery and accumulate beyond a certain threshold to cause neurotoxicity, which then leads to neuronal dysfunction, cell death and overt symptoms. Yet proteopathy-related proteins are expressed in the brain before birth.

Among these disorders, HD is caused by an expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene, which results in an abnormally long polyglutamine (polyQ) tract in the huntingtin protein. HD is characterized by the dysfunction and death of adult neurons in the cortex and the striatum. An important feature of cortico-derived circuits in HD is their early alteration. For example, cortico-striatal connections change decades before overt neurodegeneration, as revealed by neuroimaging studies of premanifest HD gene carriers. This supports the idea that developmental abnormalities may contribute to disease onset.

I will describe how HTT regulates mouse cortical development, and how polyQ HTT interferes with cortical development in HD mouse models and human mutation carrier fetuses. I will then demonstrate that there is a critical period of postnatal development early on that requires attention for future therapies. Finally, I will discuss our current research, which aims to further connect abnormal brain development with adult-onset disease in HD and other related neurological conditions.

References

      Barnat M et al (2020). Huntington disease alters human neurodevelopment. Science, 10.1126/science.aax3338.

      Capizzi M et al (2022). Developmental defects in Huntington’s disease show that axonal growth and microtubule reorganization require NUMA1. Neuron, 10.1016/j.neuron.2021.10.033.

      Braz BY et al (2022). Treating early postnatal circuit defect delays Huntington disease onset and pathology in mice. Science, 10.1126/science.abq5011.

      Carpentier R et al (2025). Structure of the Huntingtin F-actin complex reveals its role in cytoskeleton organization. Science Advances, eadw4124.