Mechanisms of Astrocytic Subtype-mediated Synaptic Impairments in Amyotrophic Lateral Sclerosis (ALS)

• Applicant: Dr. Josiane Kelly Sime Longang Siemund
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 584435661

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects both the brain and spinal cord. Neurodegenerative diseases are primarily characterized by neuronal dysfunction and death. Over the past few decades, research in this field has focused on understanding the pathological mechanisms of motor function impairments, with the aim of improving disease phenotypes and patient outcomes. In ALS, significant advances have been made in identifying pathways and biomarkers involved in the disease's pathophysiological mechanisms. There is growing evidence for the role of reactive glial cells, particularly astrocytes, in motor function deficits, highlighting their contribution to morphological changes and synaptic damage. However, the correlation between changes in these cells and synaptic deficits, as well as their impact on neuronal function at critical disease time points, remains unclear. This research proposal, therefore, aims to investigate the mechanisms by which changes in astrocytic subtypes relate to synaptic impairments and affect neuronal activity in the brain and spinal cord of ALS mice. Preliminary results reveal that spinal synaptic loss is a segment-specific event that correlates with motor neuron (MN) death in ALS mice. Additionally, synaptic loss and morphological changes were associated with astrocyte activation and motor function deficits. These initial studies provide a solid foundation for a segment-specific investigation of astrocytic subtype-mediated synaptic impairments in ALS mice. The proposal at hand will employ high-resolution microscopy, state-of-the-art electrophysiology, and further molecular biology techniques to study the impact and the pathway through which astrocytic subtypes contribute to synaptic dysfunction and loss, leading to neuronal deficits and death in ALS. These findings will not only offer novel insights into the pathological mechanisms of synaptic deficits and their contribution to the disease phenotype in ALS but also directly link changes in specific astrocytic subtypes to synaptic and neuronal dysfunction during disease progression. Ultimately, these results will enhance our understanding of the pathophysiology of ALS and suggest pathways and potential biomarkers for translational applications aimed at improving disease phenotype in ALS mice and patients.

• DFG Programme: Fellowship
• International Connection: Canada
• Host: Professorin Dr. Chantelle Sephton