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bioRxiv · 10.1101/2024.06.20.599774

Cortical synaptic vulnerabilities revealed in a α-synuclein aggregation model of Parkinson's disease

Sah, S.·Sauerbeck, A. D.·Gupta, J.·Perez-Acuna, D.·Reiber, J. E.·Russell, D.·Goralski, T.·Henderson, M.·Volpicelli-Daley, L. A.·Higley, M. J.·Kummer, T. T.·Biederer, T.
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Abstract

-Synuclein aggregates characterize -synucleinopathies, including Parkinsons disease and Dementia with Lewy bodies. A majority of people with these disorders experience cognitive decline, and its extent correlates with cortical -synuclein pathology. Mechanisms by which pathology targets cortical circuits remain to be understood so that the debilitating non-motor impairments can be addressed. Overt neuronal loss is not a major feature of cortical pathology, but a reduction of presynaptic sites has been reported at late stages of PD. We here define excitatory synapses as neuronal loci affected by -synuclein aggregation, showing that they are progressively lost, and identify temporal and spatial patterns of synaptic vulnerability. Results were obtained in a mouse model using intrastriatal injection of pre-formed -synuclein fibrils to template the aggregation of endogenous -synuclein in cortical neurons. Lewy neurite-like aggregates were predominantly observed in axons. Super-resolved imaging showed -synuclein aggregation within cortical synapses and revealed that synaptic aggregation is most severe proximal to Lewy neurite-like structures and linked to the earliest detectable loss of excitatory synapses. Excitatory synapses also exhibited ultrastructural aberrations, including a redistribution of pre- and post-synaptic protein clusters away from contact sites and reduced synaptic vesicle size. As pathology advanced, VGLUT1-positive intracortical synapses, enriched in -synuclein, were progressively vulnerable in this striatal seeding model, while VGLUT2-positive long-range synapses with minimal -synuclein were spared. Inhibitory synapses were not affected. In agreement with a disruptive role of synaptic -synuclein aggregation, super-resolved mesoscale imaging determined that synaptic but not non-synaptic -synuclein pathology is correlated with excitatory synapse loss. Physiological recordings confirmed impaired excitatory neurotransmission. Pathology propagation tracked cortical connectivity, with intra-column synapse loss correlated between interconnected layers V and II/III. Contralateral areas receiving projections from pathologic layer V also exhibited synapse loss. These findings reveal synapses as principal cellular loci of -synuclein pathology and define how molecular and circuit-based mechanisms underlie the cortical progression of synaptic pathology in -synucleinopathies.

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Sah, S., Sauerbeck, A. D., Gupta, J., Perez-Acuna, D., Reiber, J. E., Russell, D., Goralski, T., Henderson, M., Volpicelli-Daley, L. A., Higley, M. J., Kummer, T. T., Biederer, T.. 2024-06-21. Cortical synaptic vulnerabilities revealed in a α-synuclein aggregation model of Parkinson's disease. https://doi.org/10.1101/2024.06.20.599774

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