Review14-3-3 proteins in neurodegeneration
Highlights
► Nervous tissue specific cellular mechanisms involving 14-3-3. ► 14-3-3 isoforms integrate signalling in neuronal survival and death. ► Oxidative and endoplasmic reticulum stress. ► 14-3-3 association affects protein stability, aggregation and degradation. ► Involvement of 14-3-3 in a number of neurodegenerative diseases. ► 14-3-3 in Huntington's; Spinocerebellar ataxia; ALS; Parkinson's & Alzheimer's.
Introduction
Initially, 14-3-3 proteins were considered to be brain specific [1], but it turned out rapidly, that although 14-3-3 proteins display the highest expression levels in the brain, they are also present in other tissues [2]. Nowadays it is established that 14-3-3 isoforms are conserved acidic proteins that are ubiquitously expressed not only in mammalian cell types and tissues but also in all eukaryotic organisms and cells [3].
Among the first discovered functions was the ability of 14-3-3 proteins to activate tryptophan and tyrosine hydroxylases [4], [5], the rate limiting enzymes in the synthesis of serotonin and catecholamines, e.g. dopamine, respectively, pointing to the importance of 14-3-3 proteins in neuronal function. When another property of 14-3-3, namely the regulation of protein kinase C (PKC) [6], [7] was discovered it became clear that 14-3-3 proteins form homo- and heterodimers [8], [9], [10] and selectively bind to phosphoserine/threonine (pSer/Thr) motifs of target proteins [11], [12]. At present, several hundred mostly phosphorylated binding partners have been identified and through isoform specific interaction with the substrates 14-3-3 proteins are involved in many cellular processes. In addition to neuronal regulation and neurodegenerative diseases, these include several metabolic pathways, redox-regulation, transcription, RNA processing, protein synthesis, protein folding and degradation, cell cycle, cytoskeletal organization and cellular trafficking [13].
Section snippets
Neurons
14-3-3 proteins have a number of binding partners involved in the regulation of basal functions important in all cell type, e.g. protein kinases, phosphatases, or small GTPases. The particular importance of 14-3-3 proteins in nervous tissue is based on the relevance of certain processes for proper neuronal development and function, e.g. cytoskeleton reorganisation or ion channel modulation as prerequisites for axon, neurite and synapse formation, and neuronal plasticity.
In Drosophila, in the
Oxidative stress
Cellular reactions in response to oxidative stress may be a primary event in neurodegenerative diseases, as has been suggested for PD, and can also be a secondary event, e.g. elicited by protein aggregation.
14-3-3 proteins are redox-regulated proteins that bind to diverse selenoproteins. 14-3-3β and 14-3-3γ bind to selenoprotein W, which is important in defence against oxidative stress in neuronal development [56], [57]. NADPH oxidases (Nox) are catalytic components of enzyme complexes that
Huntington's disease (HD)
HD is an autosomal dominant disorder with CAG expansion in first exon of the IT15 gene. Intranuclear and intracytoplasmic inclusions of the polyQ expanded protein huntingtin can be detected. A number of proteins including 14-3-3 and α-synuclein colocalize with the perinuclear inclusions of huntingtin protein [103].
The degenerative process in HD primarily involves medium spiny striatal neurons and, to a lesser extent, cortical neurons. GABAergic and enkephalin neurons of the basal ganglia are
Conclusions
The focus of this review is the involvement of 14-3-3 in brain and neurological disease. This has developed a long way since their first description as abundant brain proteins by Moore and Perez [169]. The phosphorylation specific association with proteins involved in diverse neurodegenerative diseases leading to their accumulation in specific brain regions is now well-established as a major contributing factor.
References (169)
14-3-3 proteins: a historic overview
Semin Cancer Biol
(2006)- et al.
Brain 14-3-3 protein is an activator protein that activates tryptophan 5-monooxygenase and tyrosine 3-monooxygenase in the presence of Ca2+,calmodulin-dependent protein kinase II
FEBS Lett
(1987) - et al.
Mammalian and yeast 14-3-3 isoforms form distinct patterns of dimers in vivo
Biochem Biophys Res Commun
(2003) - et al.
Isoforms of 14-3-3 protein can form homo- and heterodimers in vivo and in vitro: implications for function as adapter proteins
FEBS Lett
(1995) Post-translational modification of 14-3-3 isoforms and regulation of cellular function
Semin Cell Dev Biol
(2011)- et al.
Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine
Cell
(1996) - et al.
Olfactory learning deficits in mutants for leonardo, a Drosophila gene encoding a 14-3-3 protein
Neuron
(1996) - et al.
Binding of alphaII spectrin to 14-3-3beta is involved in NCAM-dependent neurite outgrowth
Mol Cell Neurosci
(2010) - et al.
14-3-3 protein interacts with huntingtin-associated protein 1 and regulates its trafficking
J Biol Chem
(2007) - et al.
Modulation of inactivation properties of CaV2.2 channels by 14-3-3 proteins
Neuron
(2006)