14-3-3 proteins are a family of highly conserved proteins implicated in many cellular functions, including protein folding, protein trafficking, and cell survival. 14-3-3s are key interactors of several proteins implicated in PD, including alpha-synuclein (αsyn), parkin, and LRRK2. Disruption of 14-3-3 expression and function has been recently implicated in PD. 14-3-3s colocalize with αsyn in Lewy bodies in PD, and we have observed a reduction of 14-3-3 levels in cellular and mouse αsyn models. We have hypothesized that disruption of 14-3-3s in PD may promote the neurodegenerative process and that increasing 14-3-3 expression may slow cell loss in PD. In support of this idea, we have shown that 14-3-3 overexpression is protective in several PD models, including neurotoxin, αsyn, and LRRK2-based models, while 14-3-3 inhibition promotes toxicity. More recently, we have found an increase in 14-3-3 phosphorylation in PD brains, raising the possibility that aberrant 14-3-3 phosphorylation could promote the neurodegenerative process by disrupting 14-3-3s’ ability to regulate αsyn and LRRK2.
    Current projects in the lab are focused on understanding the mechanisms by which 14-3-3s can regulate αsyn and LRRK2 toxicity, the impact of 14-3-3 phosphorylation on function, and mechanisms that led to 14-3-3 phosphorylation in disease. We have developed several novel 14-3-3 mouse models to examine the role of 14-3-3s in PD.

Figure: 14-3-3θ delays alpha-synuclein aggregation in the preformed fibril mouse model

Key questions:

  • Do 14-3-3s regulate the release and uptake of αsyn?
  • Do 14-3-3s regulate LRRK2 toxicity?
  • Can small molecules that specifically activate 14-3-3 expression be used as potential therapeutic agent?
  • Does 14-3-3 phosphorylation promote αsyn and LRRK2 toxicity?
  • Are 14-3-3s a common underlying mechanism for other neurodegenerative disorders?
  • Do environmental toxins associated with increased Parkinson’s disease risk promote 14-3-3 dysfunction?