Neuroprotective function of 14-3-3 proteins in neurodegeneration

Abstract

14-3-3 proteins are abundantly expressed adaptor proteins that interact with a vast number of binding partners to regulate their cellular localization and function. They regulate substrate function in a number of ways including protection from dephosphorylation, regulation of enzyme activity, formation of ternary complexes and sequestration. The diversity of 14-3-3 interacting partners thus enables 14-3-3 proteins to impact a wide variety of cellular and physiological processes. 14-3-3 proteins are broadly expressed in the brain, and clinical and experimental studies have implicated 14-3-3 proteins in neurodegenerative disease. A recurring theme is that 14-3-3 proteins play important roles in pathogenesis through regulating the subcellular localization of target proteins. Here, we review the evidence that 14-3-3 proteins regulate aspects of neurodegenerative disease with a focus on their protective roles against neurodegeneration.

Figure 1

Overview of the molecular basis of the neuroprotective roles of 14-3-3 in Parkinson's disease. 14-3-3 proteins may play a protective role against neurodegeneration in PD by interacting with various proteins. (a) 14-3-3 interacts with Bad and Bax proteins and inhibits their translocation into mitochondria and their subsequent suppression of Bcl-2. These interactions prevent apoptosis of neurons. (b) 14-3-3 proteins interact with phosphorylated tyrosine hydroxylase (TH) to enhance its activity. In contrast, α-synuclein binds unphosphorylated TH to reduce its activity. These protein interactions contribute to the maintenance of optimal dopamine levels. Inadequate levels of dopamine lead to a neurodegeneration. (c) 14-3-3 interacts with LRRK2 protein that is related to PD pathogenesis. This interaction may inhibit cytosolic accumulation and secretion of LRRK2. (d) α-synuclein interacts with 14-3-3 proteins and forms aggregates, resulting in the sequestration of 14-3-3. This sequestration may contribute to the pathogenesis of PD.

Figure 2

Overview of the molecular basis of 14-3-3 antiapoptotic activity. 14-3-3 proteins inhibit apoptosis through multiple mechanisms including regulating the subcellular localization of pro- and antiapoptotic proteins. 14-3-3 binds to Bad and Bax to sequester them in the cytoplasm. Similarly, SRPK2 and FOXO1 are retained in the cytoplasm through 14-3-3 binding. Cdc25 is exported from the nucleus through a 14-3-3 interaction. SRPK2, FOXO1, and Cdc25 contribute to cell cycle reentry and subsequent apoptosis. Further, the death-promoting activity of ASK1 is antagonized by its binding to 14-3-3 proteins.