Perry, Elaine K

Publication Detail

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Co-ordinate transcriptional regulation of dopamine synthesis genes by alpha-synuclein in human neuroblastoma cell lines.

Melisa J Baptista; Casey O'Farrell; Sneha Daya; Rili Ahmad; David W Miller; John Hardy; Matthew J Farrer; Mark R Cookson (Profiled Author: Hardy, John)

Laboratory of Neurogenetics, National Institute on Aging/NIH, Building 10 Room 6C103, MSC 1589, 9000 Rockville Pike, Bethesda, MD 20892, USA. baptista@mail.nih.gov
Journal of neurochemistry 2003;85(4):957-68.

Abnormal accumulation of alpha-synuclein in Lewy bodies is a neuropathological hallmark of both sporadic and familial Parkinson's disease (PD). Although mutations in alpha-synuclein have been identified in autosomal dominant PD, the mechanism by which dopaminergic cell death occurs remains unknown. We investigated transcriptional changes in neuroblastoma cell lines transfected with either normal or mutant (A30P or A53T) alpha-synuclein using microarrays, with confirmation of selected genes by quantitative RT-PCR. Gene products whose expression was found to be significantly altered included members of diverse functional groups such as stress response, transcription regulators, apoptosis-inducing molecules, transcription factors and membrane-bound proteins. We also found evidence of altered expression of dihydropteridine reductase, which indirectly regulates the synthesis of dopamine. Because of the importance of dopamine in PD, we investigated the expression of all the known genes in dopamine synthesis. We found co-ordinated downregulation of mRNA for GTP cyclohydrolase, sepiapterin reductase (SR), tyrosine hydroxylase (TH) and aromatic acid decarboxylase by wild-type but not mutant alpha-synuclein. These were confirmed at the protein level for SR and TH. Reduced expression of the orphan nuclear receptor Nurr1 was also noted, suggesting that the co-ordinate regulation of dopamine synthesis is regulated through this transcription factor.

3 Originating Grant

• 1.

  Hardy, John A

  GENETICS AND MOLECULAR BIOLOGY OF PARKINSONISM

  30 September 1999 - 31 July 2004

  NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

  Total Funding: $ 3,886,270

• 2.

  Dickson, Dennis William

  Genetics and Molecular Biology of Parkinsonism

  30 September 1999 - 31 August 2009

  NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

  Total Funding: $ 8,904,777

• 3.

  Dickson, Dennis W

  GENETICS AND MOLECULAR BIOLOGY OF PARKINSONISM

  30 September 1999 - 29 September 2004

  NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

  Total Funding: $ 2,454,521

Scientific Context

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