%0 Journal Article
%T ⍺-Synuclein levels in Parkinson's disease - Cell types and forms that contribute to pathogenesis.
%A Sagredo GT
%A Tanglay O
%A Shahdadpuri S
%A Fu Y
%A Halliday GM
%J Exp Neurol
%V 379
%N 0
%D 2024 Sep 14
%M 39009177
%F 5.62
%R 10.1016/j.expneurol.2024.114887
%X Parkinson's disease (PD) has two main pathological hallmarks, the loss of nigral dopamine neurons and the proteinaceous aggregations of ⍺-synuclein (⍺Syn) in neuronal Lewy pathology. These two co-existing features suggest a causative association between ⍺Syn aggregation and the underpinning mechanism of neuronal degeneration in PD. Both increased levels and post-translational modifications of ⍺Syn can contribute to the formation of pathological aggregations of ⍺Syn in neurons. Recent studies have shown that the protein is also expressed by multiple types of non-neuronal cells in the brain and peripheral tissues, suggesting additional roles of the protein and potential diversity in non-neuronal pathogenic triggers. It is important to determine (1) the threshold levels triggering ⍺Syn to convert from a biological to a pathologic form in different brain cells in PD; (2) the dominant form of pathologic ⍺Syn and the associated post-translational modification of the protein in each cell type involved in PD; and (3) the cell type associated biological processes impacted by pathologic ⍺Syn in PD. This review integrates these aspects and speculates on potential pathological mechanisms and their impact on neuronal and non-neuronal ⍺Syn in the brains of patients with PD.