Synuclein knockout mice are viable

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Asa Abeliovich, Y. Schmitz, I. Fariñas, D. Choi-Lundberg, W.-H. Ho, P. E. Castillo, N. Shinsky, J. M. Verdugo, M. Armanini, A. Ryan, M. Hynes, H. Phillips, D. Sulzer and A. Rosenthal (first affiliation: Department of Neurology, University of California, San Francisco). Neuron 25(1):239–252, 2000. Funders were not read.

What happened

After the synuclein gene SNCA was linked to Parkinson's (landmark 4), a basic question was what the protein does and whether the body needs it. The team deleted both copies of the gene in mice. The paper's title reports "functional deficits in the nigrostriatal dopamine system": the changes were in how the dopamine circuit behaved, not in whether the animals or their dopamine neurons survived. The knockout mice were viable and fertile, with intact brain architecture and a normal count of dopamine cell bodies, fibres and synapses. Dopamine release and reuptake after a single electrical pulse were normal, but release rose with paired pulses (mimicked by raised calcium), striatal dopamine was reduced, and the locomotor response to amphetamine was weaker. The authors proposed that synuclein is a presynaptic, activity-dependent brake on dopamine signalling.

Why it moved us toward a cure

If a drug is to cut synuclein, the body must tolerate having less of it. This mouse is the first evidence that it can. It supports the safety case for the synuclein-lowering drugs in landmark 29, which rests on extra copies of the gene causing disease (landmark 14).

Outcome

Advanced. Complete lifelong loss in mice does not prove a drug that lowers synuclein by a fraction in adults is safe.

Sources

• Abeliovich et al., Neuron 2000, DOI 10.1016/s0896-6273(00)80886-7 (abstract read via Europe PMC, PMID 10707987)
• Not yet verified: lifespan and the size of the dopamine reduction; the later knockout and knock-down literature (not reviewed); funders.