Motor neuron disease (MND) is a fatal neurodegenerative disorder characterised by the progressive degeneration of motor neurons in the central nervous system. Synaptic dysfunction is increasingly recognised as an early feature of MND, with evidence from animal models, in vitro studies, and electrophysiological analyses suggesting that synaptic alterations can occur before overt neuronal loss. However, the molecular mechanisms underlying synaptic dysfunction and loss remain poorly understood.

We recently used high-throughput synaptic proteomic profiling of the most severely affected brain regions and identified area-specific expression trajectories and distinct protein signatures (Laszlo et al 2022, Aly & Laszlo et al 2023). Importantly, stratification by clinical and genetic features revealed distinct synaptic signatures associated with cognitive impairment and C9ORF72 repeat expansion. However, these studies provided limited insight into the earliest molecular changes associated with synaptic dysfunction.

Taking advantage of brain regions that are relatively spared from overt neuronal degeneration, we hypothesised that these areas may retain earlier synaptic phenotypes, providing an opportunity to identify the earliest molecular changes associated with MND. Using  postmortem visual cortical tissue of MND cases, we performed deep synaptic proteomic profiling alongside high-resolution imaging approaches, including array tomography and electron microscopy. We identified disruption of synaptic vesicle cycling and neurotransmission as prominent molecular features of MND synapses. Importantly, these alterations were evident in the absence of substantial neuronal loss, supporting their emergence as an early feature of disease pathology.

We also identified degeneration of associated white matter regions, characterised by disrupted myelin architecture and reactive gliosis. These findings suggest that impaired afferent axonal integrity may contribute to early cortical synaptic dysfunction and highlight the potential importance of circuit-level pathology in the spread of MND.

Together, these studies provide a molecular and structural map of the human MND synapse and demonstrate that synaptic pathology extends beyond the most severely affected motor regions. They highlight alterations in presynaptic signalling, neurotransmission, and glutamatergic pathways as potential early features of MND, while demonstrating how cognitive phenotype and C9ORF72 genotype shape the synaptic proteome. Collectively, the findings support the synapse as an early and potentially modifiable target in MND.

More information:

• https://discovery.dundee.ac.uk/en/persons/zsofia-laszlo/