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SNCA

alpha-synuclein

Definition: Alpha (alpha)-synuclein (SNCA) is a presynaptic protein. Abnormal expression of which has been associated with neurodegenerative and neoplastic diseases.

Alpha-synuclein is a highly conserved protein of 140 amino acids, that is expressed predominantly in neurons and is particularly abundant in presynaptic terminals. Alpha-synuclein might have a role in synaptic plasticity and might modulate DOPAMINERGIC neuro-transmission.

Pathoogy

- SNCA germline mutations in

  • dominant Parkinson disease
  • early-onset Parkinson disease

Two amino-acid substitutions in alpha-synuclein, A53T and A30P, are associated with autosomal-dominant, early-onset Parkinson disease. The mutant alpha-synuclein protein accumulates as intracytoplasmic inclusions in neurons to form the Lewy bodies that are characteristic of this condition. Structural studies have shown that the A30P mutant favours the formation of oligomers rather than fibrils, and that these small intermediates could be the toxic species that cause cell death and the associated neurodegenerative disease.

- SNCA triplication in cardiac denervation and Parkinson disease (parkinsonism) (14736756, 14593171)

See also

- synucleinopathies
- serpinopathies
- conformational diseases

- 8 mutated Parkinson genes known (2008)

SNCA PARK2 UCHL1 PINK1 DJ1 LRRK2 ATP13A2 HTRA2

Reviews

- Raghavan R, Kruijff L, Sterrenburg MD, Rogers BB, Hladik CL, White CL 3rd. Alpha-synuclein expression in the developing human brain. Pediatr Dev Pathol. 2004 Sep-Oct;7(5):506-16. PMID: 15547775

- Maries E, Dass B, Collier TJ, Kordower JH, Steece-Collier K. The role of alpha-synuclein in Parkinson?s disease: insights from animal models. Nat Rev Neurosci. 2003 Sep;4(9):727-38. PMID: 12951565

- Shimohama S, Sawada H, Kitamura Y, Taniguchi T. Disease model: Parkinson?s disease. Trends Mol Med. 2003 Aug;9(8):360-5. PMID: 12928038

- Alves da Costa C. Recent advances on alpha-synuclein cell biology: functions and dysfunctions. Curr Mol Med. 2003 Feb;3(1):17-24. PMID: 12558071

- Lomas DA, Carrell RW. Serpinopathies and the conformational dementias. Nat Rev Genet. 2002 Oct ;3(10):759-68. PMID : 12360234

- Lotharius J, Brundin P. Pathogenesis of Parkinson?s disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci. 2002 Dec;3(12):932-42. PMID: #12461550

- Lotharius J, Brundin P. Impaired dopamine storage resulting from alpha-synuclein mutations may contribute to the pathogenesis of Parkinson?s disease. Hum Mol Genet. 2002 Oct 1;11(20):2395-407. PMID: 12351575

- Farrer M, Gwinn-Hardy K, Hutton M, Hardy J. The genetics of disorders with synuclein pathology and parkinsonism. Hum Mol Genet. 1999;8(10):1901-5. PMID: 10469843

- Goedert M. Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci. 2001 Jul;2(7):492-501. PMID: 11433374

References

- Singleton A, Gwinn-Hardy K, Sharabi Y, Li ST, Holmes C, Dendi R, Hardy J, Singleton A, Crawley A, Goldstein DS. Association between cardiac denervation and parkinsonism caused by alpha-synuclein gene triplication. Brain. 2004 Apr;127(Pt 4):768-72. PMID: 14736756

- Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K. alpha-Synuclein locus triplication causes Parkinson?s disease. Science. 2003 Oct 31;302(5646):841. PMID: 14593171