α-Synuclein Shares Physical and Functional Homology with 14-3-3 Proteins

α-Synuclein has been implicated in the pathophysiology of many neurodegenerative diseases, including Parkinson’s disease (PD) and Alzheimer’s disease. Mutations in α-synuclein cause some cases of familial PD (Polymeropoulos et al., 1997; Kruger et al., 1998). In addition, many neurodegenerative diseases show accumulation of α-synuclein in dystrophic neurites and in Lewy bodies (Spillantini et al., 1998). Here, we show that α-synuclein shares physical and functional homology with 14-3-3 proteins, which are a family of ubiquitous cytoplasmic chaperones. Regions of α-synuclein and 14-3-3 proteins share over 40% homology. In addition, α-synuclein binds to 14-3-3 proteins, as well as some proteins known to associate with 14-3-3, including protein kinase C, BAD, and extracellular regulated kinase, but not Raf-1. We also show that overexpression of α-synuclein inhibits protein kinase C activity. The association of α-synuclein with BAD and inhibition of protein kinase C suggests that increased expression of α-synuclein could be harmful. Consistent with this hypothesis, we observed that overexpression of wild-type α-synuclein is toxic, and overexpression of α-synuclein containing the A53T or A30P mutations exhibits even greater toxicity. The activity and binding profile of α-synuclein suggests that it might act as a protein chaperone and that accumulation of α-synuclein could contribute to cell death in neurodegenerative diseases.

[1]  F. Corpet.  Multiple sequence alignment with hierarchical clustering. , 1988, Nucleic acids research.

[2]  E. Masliah,et al.  Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Michel Goedert,et al.  Identification of two distinct synucleins from human brain , 1994, FEBS letters.

[4]  R. Tremblay,et al.  Evidence that the activation of an inactive pool of membrane-associated protein kinase C is linked to the IL-2-dependent survival of T lymphocytes. , 1994, Journal of immunology.

[5]  C. Behl,et al.  Amyloid β peptide induces necrosis rather than apoptosis , 1994, Brain Research.

[6]  S. Korsmeyer,et al.  Bad, a heterodimeric partner for Bcl-xL and Bcl-2, displaces bax and promotes cell death , 1995, Cell.

[7]  David F. Clayton,et al.  Characterization of a novel protein regulated during the critical period for song learning in the zebra finch , 1995, Neuron.

[8]  A. Aitken,et al.  Identification of 14-3-3 proteins in human platelets: effects of synthetic peptides on protein kinase C activation. , 1996, The Biochemical journal.

[9]  P. Allen,et al.  Interaction of 14-3-3 with Signaling Proteins Is Mediated by the Recognition of Phosphoserine , 1996, Cell.

[10]  M. Polymeropoulos,et al.  Mapping of a Gene for Parkinson's Disease to Chromosome 4q21-q23 , 1996, Science.

[11]  X. Chen,et al.  RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease , 1996, Nature.

[12]  Elizabeth Yang,et al.  Serine Phosphorylation of Death Agonist BAD in Response to Survival Factor Results in Binding to 14-3-3 Not BCL-XL , 1996, Cell.

[13]  G. Reuther,et al.  The roles of 14-3-3 proteins in signal transduction. , 1996, Vitamins and hormones.

[14]  J. Lowe,et al.  Neurofibrillary tangles of Alzheimer's disease brains contain 14-3-3 proteins , 1996, Neuroscience Letters.

[15]  P. Lansbury,et al.  NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. , 1996, Biochemistry.

[16]  T. L. Collins,et al.  Direct interaction between protein kinase C theta (PKC theta) and 14-3-3 tau in T cells: 14-3-3 overexpression results in inhibition of PKC theta translocation and function , 1996, Molecular and cellular biology.

[17]  A Aitken,et al.  Structure and Sites of Phosphorylation of 14-3-3 Protein: Role in Coordinating Signal Transduction Pathways , 1997, Journal of protein chemistry.

[18]  M. Yaffe,et al.  The Structural Basis for 14-3-3:Phosphopeptide Binding Specificity , 1997, Cell.

[19]  T. Isobe,et al.  The 14‐3‐3 protein binds its target proteins with a common site located towards the C‐terminus , 1997, FEBS letters.

[20]  A. Aitken,et al.  14-3-3 inhibits the Dictyostelium myosin II heavy-chain-specific protein kinase C activity by a direct interaction: identification of the 14-3-3 binding domain. , 1997, Molecular biology of the cell.

[21]  Y Agid,et al.  Nuclear translocation of NF-kappaB is increased in dopaminergic neurons of patients with parkinson disease. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Ronald L. Davis,et al.  Leonardo, a Drosophila 14-3-3 Protein Involved in Learning, Regulates Presynaptic Function , 1997, Neuron.

[23]  J Q Trojanowski,et al.  Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble α‐synuclein , 1998, Annals of neurology.

[24]  Xudong Huang,et al.  Dramatic Aggregation of Alzheimer Aβ by Cu(II) Is Induced by Conditions Representing Physiological Acidosis* , 1998, The Journal of Biological Chemistry.

[25]  R. Jakes,et al.  Effects of the mutations Ala30 to Pro and Ala53 to Thr on the physical and morphological properties of α‐synuclein protein implicated in Parkinson's disease , 1998, FEBS letters.

[26]  David F. Clayton,et al.  The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease , 1998, Trends in Neurosciences.

[27]  D. Neill,et al.  Aggregates from mutant and wild‐type α‐synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of β‐sheet and amyloid‐like filaments , 1998, FEBS letters.

[28]  M. Goedert,et al.  Binding of α-Synuclein to Brain Vesicles Is Abolished by Familial Parkinson’s Disease Mutation* , 1998, The Journal of Biological Chemistry.

[29]  A. Jonas,et al.  Stabilization of α-Synuclein Secondary Structure upon Binding to Synthetic Membranes* , 1998, The Journal of Biological Chemistry.

[30]  S. Paik,et al.  Self‐oligomerization of NACP, the precursor protein of the non‐amyloid β/A4 protein (Aβ) component of Alzheimer's disease amyloid, observed in the presence of a C‐terminal Aβ fragment (residues 25–35) , 1998 .

[31]  Olaf Riess,et al.  AlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease , 1998, Nature Genetics.

[32]  Makoto Hashimoto,et al.  Human recombinant NACP/α-synuclein is aggregated and fibrillated in vitro: Relevance for Lewy body disease , 1998, Brain Research.

[33]  W. Honer,et al.  Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. , 1998, The American journal of pathology.

[34]  R. Krüger,et al.  Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. , 1998, Nature genetics.

[35]  Joseph Avruch,et al.  A dimeric 14-3-3 protein is an essential cofactor for Raf kinase activity , 1998, Nature.

[36]  Peter T. Lansbury,et al.  Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease , 1998, Nature Medicine.

[37]  A. Morris,et al.  Regulation of phospholipase D2: selective inhibition of mammalian phospholipase D isoenzymes by alpha- and beta-synucleins. , 1998, Biochemistry.

[38]  R. Crowther,et al.  α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies , 1998 .

[39]  L. Kauvar,et al.  Modulating protein kinase C signal transduction. , 1998, Advances in pharmacology.