Servicenavigation

Project Details

Back

Projekt Print View

Cellular and Circuit Mechanisms of Upper Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis (ALS)

Subject Area Molecular and Cellular Neurology and Neuropathology
Clinical Neurology; Neurosurgery and Neuroradiology
Term from 2017 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 326014787
 
Final Report Year 2025

Final Report Abstract

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of upper motor neurons (UMNs) in the motor cortex and lower motor neurons (LMNs) in spinal cord. While LMN degeneration has been extensively studied, the mechanisms underlying UMN vulnerability remain poorly understood. Emerging evidence suggests that UMN dysfunction may precede and drive LMN degeneration, with cortical hyperexcitability - a hallmark of ALS observed in patients and animal models - occurring before motor symptom onset and correlating with disease severity. This hyperexcitability implies that altered neuronal excitability or activity plays a critical role in disease pathogenesis. This research project investigated cellular and circuit mechanisms of UMN degeneration using advanced in vivo imaging, behavioral tracking, and molecular approaches in ALS mouse models (SOD1G93A and FUSdNLS). In vivo two-photon imaging revealed that UMNs in SOD1G93A mice exhibit fewer synapses even at presymptomatic stages, with remaining synapses showing enlarged spine heads (via chronic STED imaging) and reduced structural dynamics, suggesting increased glutamatergic input and impaired network flexibility. Concurrently, in vivo calcium imaging detected hyperresponsiveness to locomotion in neurons in cortical layers 2/3 and 5 during early symptomatic stages. Presymptomatically, hyperresponsiveness was restricted to layer 2/3 pyramidal neurons, which provide input to UMNs in layer 5. Chemogenetic silencing of layer 2/3 neurons delayed disease onset and improved late-stage motor function, supporting a feedforward translaminar excitation model where layer 2/3 hyperactivity drives UMN dysfunction. In a collaborative study we identified reduced noradrenergic innervation and release in ALS models and patients, implicating noradrenergic deficits in circuit dysfunction. Astrocytes, key regulators of synaptic health, also showed compromised calcium signaling in behaving mice, partly due to diminished noradrenaline. Molecular profiling revealed sex-specific changes, such as downregulation of TMEM259 (an ER stress regulator) in female SOD1G93A mice. Restoring TMEM259 via astrocyte-specific AAVs boosted EAAT2 expression and preserved LMNs in female mice. Similarly, genetically rescuing the FUSdNLS mutation in astrocytes normalized calcium signaling and locomotor hyperactivity in FUSdNLS mice. These findings underscore the interplay of synaptic instability, cortical hyperexcitability, astrocyte dysfunction, and noradrenergic deficits in ALS progression. Therapeutic strategies targeting layer 2/3 hyperactivity, noradrenergic pathways, or astrocyte-specific mechanisms show promise for modulating disease trajectories. Future studies must unravel the molecular drivers of these circuit alterations and refine cell-type-specific interventions tailored to disease stages.

Publications

 
 

Additional Information

© 2026 DFG Disclaimer / Copyright / Privacy Policy

Textvergrößerung und Kontrastanpassung