RESEARCH: Synuclein-protein complexes render dopamine neurotoxic

July 10, 2002

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Synuclein-protein complexes render dopamine neurotoxic

NEW YORK (Reuters Health) - Alpha-synuclein forms soluble complexes with

the anti-apoptotic protein 14-3-3 that appear to cause endogenous dopamine

to become toxic to neurons in the substantia nigra, according to a study in

the June issue of Nature Medicine.

This finding may explain the selective loss of dopaminergic neurons in

Parkinson's disease, the study authors suggest, and it may ultimately lead

to new therapies for the disease, as well as for diffuse Lewy-body disease

and some variants of Alzheimer's disease.

Dr. Bruce A. Yankner, of the Children's Hospital in Boston, told Reuters

Health that " until now, the combination of alpha-synuclein with 14-3-3

protein was not known to cause neuron degeneration. "

Dr. Yankner and associates found that transfection of alpha-synuclein in

primary cultures of nondopaminergic human cortical neurons (HCN cells) and

in human fetal dopaminergic neurons (DAN cells) led to similar expression

of the protein.

Overexpression of alpha-synuclein increased survival of the HCN cells, but

led to increased apoptosis in the DAN cells.

They then inhibited endogenous dopamine expression in DAN cells and found

that apoptosis induced by alpha-synuclein and potentiated by oxidative

stress was completely blocked.

Autopsy studies showed that alpha-synuclein in the substantia nigra was

complexed with 14-3-3 protein.

This inactivates the anti-apoptotic effect of 14-3-3 protein, and dopamine

metabolism subsequently promotes apoptosis by acting as a source of

reactive oxygen species, the authors suggest.

They believe that the complexes may also increase neuronal vulnerability to

other pro-oxidative agents, such as amyloid beta-protein.

" It is too early to make any clear predictions regarding treatment, " said

Dr. Yankner.

" However, if the findings of this paper prove to be important for

Parkinson's disease, then preventing alpha-synuclein from getting together

with the 14-3-3 protein could be a new therapeutic approach to the disease. "

Last Updated: 2002-05-31 14:17:45 -0400 (Reuters Health)

By Karla Gale

Nat Med 2002;8:600-606.

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