Sunday, May 11, 2025
5/11/2025
14-3-3 phosphorylation in Parkinson's disease - PROJECT SUMMARY Two critical proteins linked to Parkinson’s disease (PD) are alpha-synuclein (αsyn) and LRRK2. Mutations in either gene cause autosomal dominant forms of PD, and GWAS studies have pointed to variants in both genes as risk factors for developing idiopathic PD. Although both proteins lead to a similar pathological outcome, how these two proteins cause neuronal injury and how they interact in the disease process are not well understood. Our key discovery is that 14-3-3θ is a major regulator of both αsyn and LRRK2 and could be the missing link between αsyn and LRRK2. 14-3-3s are multifunctional, highly expressed brain proteins that act as chaperones, affect protein trafficking, and modulate enzymatic activity of their binding partners. Our research has highlighted the role of these critical proteins in PD and their interplay with both αsyn and LRRK2. We have observed that 14-3-3θ acts as a chaperone to reduce αsyn aggregation and cell-to-cell transmission, and this same 14-3-3 isoform reduces the kinase activity and toxicity of mutant LRRK2. While our data clearly points to a potentially critical role for 14-3-3 dysfunction in Parkinson’s disease, a key question that remains is how 14-3-3θ’s endogenous functions could become impaired in PD. We propose that aberrant phosphorylation of 14-3-3θ is the critical pathophysiologic event, and that increases in 14-3-3θ phosphorylation promotes LRRK2 and αsyn effects in disease. In support of this hypothesis, we recently published data showing that 14-3-3θ phosphorylation at S232 is dramatically elevated in the detergent-insoluble fractions from human PD and DLB brains. This increase in S232 phosphorylation correlates with cognitive decline and pathological severity measures, consistent with a role of S232 phosphorylation in the pathogenesis of neurodegeneration. In addition, we have observed that mitochondrial stress promotes 14-3-3θ phosphorylation at S232 in culture. The S232D phosphomimetic mutant loses its protective effects in neurotoxin and αsyn culture models. Based on these data, we hypothesize that oxidative stress is a key upstream inducer of excessive 14-3-3θ phosphorylation, leading to αsyn and LRRK2 toxicity. We recently created a conditional knock-in (KI) 14-3-3θ S232D mouse line that will serve as the critical tool to understand the impact of 14-3-3 phosphorylation in PD. In Aim 1, we will test how 14-3-3θ phosphorylation alters interactions with αsyn and modulates subsequent αsyn pathology. In Aim 2, we will test the impact of 14-3-3 phosphorylation on its interaction with LRRK2 and LRRK2 function. In Aim 3, we will examine whether 14-3-3θ phosphorylation occurs early in sporadic PD and whether oxidative stress mediates toxicity via excessive 14-3-3 phosphorylation.
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