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14-3-3 proteins in the nervous system

Nature Reviews Neuroscience volume 4, pages 752–762 (2003)Cite this article

Key Points

  • 14-3-3 proteins are involved in the control of the cell cycle, transcription and apoptosis. Owing to their multiple interactions with various kinases, receptors, enzymes and structural and cytoskeletal proteins. Although the precise role of 14-3-3 proteins is not fully understood, they seem to control the subcellular localization of proteins and to function as adaptor molecules, stimulating protein–protein interactions.

  • There are seven known members of the 14-3-3 family, but genomic analysis points to the existence of several more. Crystallographic analysis of 14-3-3 proteins has led to the elucidation of their three-dimensional topology, and the identification of the domains that are involved in their dimerization and in their interaction with ligands.

  • The function of 14-3-3 proteins in the brain remains obscure, but they seem to participate in various physiological cellular processes such as signalling, cell growth, division, adhesion, differentiation, apoptosis and regulation of ion channels.

  • The presence of 14-3-3 proteins in the cerebrospinal fluid of people with Creutzfeldt–Jakob disease has prompted the suggestions that these proteins might be involved in the pathogenesis of this condition and that they might serve as disease biomarkers. Although it is not clear yet whether these suggestions correspond to reality, 14-3-3 proteins have also been implicated in other conditions such as Alzheimer's and Parkinson's diseases, and spinocerebellar ataxia type 1.

  • Future studies should focus on defining the precise roles of 14-3-3 proteins in neuronal physiology, and should try to obtain evidence for a causal relationship between the activity of 14-3-3 proteins and the disease states in which they have been implicated.

Abstract

14-3-3 proteins are abundantly expressed in the brain and have been detected in the cerebrospinal fluid of patients with different neurological disorders. Although the function of this family of highly conserved proteins is not completely known, recent evidence indicates their involvement in multiple cellular processes. By their interaction with more than 100 binding partners, 14-3-3 proteins modulate the action of proteins that are involved in cell cycle and transcriptional control, signal transduction, intracellular trafficking and regulation of ion channels. The study of some of these interactions is sheding light on the role of 14-3-3 proteins in processes such as apoptosis and neurodegeneration.

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Figure 1: Structure of a 14-3-3 dimer.
Figure 2: Phylogenetic tree of human 14-3-3 isoforms.
Figure 3: General role of 14-3-3 proteins in the mitogen-activated protein kinase (MAPK) pathway.
Figure 4: Role of 14-3-3 proteins in apoptosis.
Figure 5: Immunostaining of Lewy bodies in pigmented neurons of a patient with Parkinson's disease.
Figure 6: Involvement of 14-3-3 proteins in dopamine synthesis and neurodegeneration.

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Acknowledgements

We thank R. Liddington for his helpful support and for providing figure 1. Our studies on 14-3-3 proteins have been supported by the Fortuene programme of the University of Tübingen and the FORUN programme of the University of Rostock.

Author information

Authors and Affiliations

  1. Department of Medical Genetics, Institute for Human Genetics, University of Tübingen, Calwerstrasse 7, Tübingen, 72076, Germany

    Daniela Berg & Olaf Riess

  2. Hertie Institute for Brain Research, Röntgenweg 11, Tübingen, 72076, Germany

    Daniela Berg

  3. Department of Medical Genetics, University of Rostock, Rembrandtstrasse 16/17, Rostock, 18057, Germany

    Carsten Holzmann

Authors
  1. Daniela Berg
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Correspondence to Daniela Berg.

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DATABASES

LocusLink

14-3-3β

14-3-3γ

14-3-3ε

14-3-3η

14-3-3ζ

14-3-3σ

14-3-3τ/θ

Genbank

XP_086931

XP_170226

XP_016044

XP_070972

XP_005100

XP_018019

XP_062204

XP_018019

XP_066597

XP_066543

Glossary

DEAE-CELLULOSE CHROMATOGRAPHY

Type of ion-exchange chromatography in which the diethylaminoethyl group acts as a weak base, allowing the binding of negatively charged molecules.

STARCH-GEL ELECTROPHORESIS

Form of electrophoresis in which starch is used as solid matrix. It is particularly useful for the separation of the allelic variants of a protein.

NONSENSE MUTATION

A mutation that results in the introduction of a stop codon to cause the premature termination of the protein.

MISSENSE MUTATION

A mutation that results in the substitution of an amino acid in a protein.

ZINC FINGER

A protein module in which cysteine or cysteine–histidine residues coordinate a zinc ion. Zinc fingers are often used in DNA recognition and in protein–protein interactions.

OUTWARDLY-RECTIFYING K+ CHANNELS

Potassium channels through which ions flow more easily out of than into the cell. They are important for membrane repolarization after an action potential.

DYNAMIN

A GTPase that takes part in endocytosis. It seems to be involved in severing the connection between the nascent vesicle and the donor membrane.

LEAK CHANNELS

Proteins that are responsible for the background membrane currents that are present at rest and that rise instantly to a new steady level in response to voltage changes.

LISSENCEPHALY

Literally meaning 'smooth brain', lissencephaly is a human brain disorder that is characterized by absence or reduction of the cerebral convolutions.

RETT SYNDROME

An inherited, X-linked neurological disorder that is lethal to males. In females, the disorder is characterized by rapid neurological deterioration that leads to dementia, autism, loss of speech and voluntary movement, and microcephaly. Rett syndrome is related to mutations in Mecp2, which encodes a methyl-CpG binding protein that acts as a transcriptional repressor.

RASMUSSEN'S ENCEPHALITIS

A progressive neurological disorder characterized by frequent and severe seizures, loss of motor skills and speech, paralysis on one side of the body, inflammation of the brain, dementia and mental deterioration. The disorder, which affects a single cerebral hemisphere, generally occurs in children under the age of 10, and is related to the production of glutamate receptor autoantibodies.

SCHILDER'S DISEASE

Also known as diffuse sclerosis, Schilder's disease is a progressive demyelinating disorder that commonly begins in childhood. Its symptoms include dementia, aphasia, seizures, personality changes, loss of balance, weakness, and vision and speech impairment. This disorder is a variant of multiple sclerosis.

NEUROLEPTIC

This term was originally coined to refer to the effects of early antipsychotic agents on cognition and behaviour.

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Berg, D., Holzmann, C. & Riess, O. 14-3-3 proteins in the nervous system. Nat Rev Neurosci 4, 752–762 (2003). https://doi.org/10.1038/nrn1197

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