Objective: To identify the cell death pathway(s) activated by α-synuclein (α-syn) pathology in an in vitro model of Lewy pathology and determine if neuronal subpopulations differ in their responses.

Background: Both apoptotic and non-apoptotic cell death pathways have been suggested to cause neuron loss in PD. Identifying the cell death mechanisms causing neurodegeneration has proven to be difficult as few model recapitulate intracellular α-syn aggregates that typify PD and neuronal loss. Using pre-formed fibrils of α-syn (PFFs) to seed pathology in neuronal cultures, we have developed a system for interrogating the cellular events and toxicity following the formation of α-syn inclusions.

Methods: Primary hippocampal cultures from E16-E18 CD1 and SncaKO mice were treated with PFFs prepared from recombinant α-syn monomer. Neurons were seeded at DIV7 with 5ug/ml of sonicated PFFs and incubated for up to 19 days post seeding. Cell viability and pathology formation were assessed at different time points by immunostaining for the neuronal marker NeuN and pSer129 α-syn, respectively. Antibodies against selective transcription factors were used to determine the effects of α-syn pathology on different subpopulations.

Results: PFF treatment reproducibly caused neuron loss in wildtype but not SncaKO neurons. Cultures treated with soluble monomeric α-syn did not display cell loss, indicating that toxicity results from the conversion of cellular α-syn by a misfolded fibrillar seed. We further show that glutamatergic neurons are selectively lost whereas other subtypes are resistant to PFF induced toxicity.

Conclusions: Our data quantitatively demonstrate that intracellular α-syn inclusions induced by PFFs lead to cell death in selective neuronal populations. Ongoing studies will decipher the mechanisms by which specific subpopulations of neurons are resistant or susceptible to pathology formation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/differential-vulnerability-to-synuclein-pathology-among-neuronal-subpopulations/