Review
14-3-3 proteins in neurodegeneration

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Abstract

Among the first reported functions of 14-3-3 proteins was the regulation of tyrosine hydroxylase (TH) activity suggesting a possible involvement of 14-3-3 proteins in Parkinson's disease. Since then the relevance of 14-3-3 proteins in the pathogenesis of chronic as well as acute neurodegenerative diseases, including Alzheimer's disease, polyglutamine diseases, amyotrophic lateral sclerosis and stroke has been recognized. The reported function of 14-3-3 proteins in this context are as diverse as the mechanism involved in neurodegeneration, reaching from basal cellular processes like apoptosis, over involvement in features common to many neurodegenerative diseases, like protein stabilization and aggregation, to very specific processes responsible for the selective vulnerability of cellular populations in single neurodegenerative diseases.

Here, we review what is currently known of the function of 14-3-3 proteins in nervous tissue focussing on the properties of 14-3-3 proteins important in neurodegenerative disease pathogenesis.

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.

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