Alzheimer’s Disease Linked to Mitochondrial Damage

Stuart A. Lipton, MD, Ph.D.,
Burnham Institute for Medical Research
NIEHS Grant P01ES016738

New research findings suggest that preventing S-nitrosylation of the mitochondrial protein Drp1 by the free radical nitric oxide may reduce or even prevent neurodegeneration in Alzheimer’s patients. This finding comes from NIEHS-supported scientists at the Burnham Institute for Medical Research in La Jolla, California.

The research team found that S-nitrosylated Drp1 facilitates mitochondrial fragmentation which leads to synaptic injury and eventual nerve cell death. This finding helps to explain how beta-amyloid protein causes neurodegeration. Beta-amyloid protein is the source of the nitric oxide which reacts with Drp1. By identifying Drp1 as the protein responsible for the synaptic injury, the investigators have discovered a new target for developing drugs that may stop or slow the progression of Alzheimer’s.

Drp1 is an enzyme that mediates fission or fragmentation of mitochondria. The team showed that excessive nitric oxide production caused damage to Drp1 which lead to excessive mitochondrial fragmentation in cultured nerve cells. Elevated levels of S-nitrosylated Drp1 were also found in the brains of Alzheimer’s patients, but not in those with Parkinson’s disease or controls who didn’t have neurodegenerative disease, adding additional evidence to the in vitro findings.

Finally, experiments to decrease Drp1 activity, either using RNA interference or a mutation that prevented Drp1 activity, inhibited excess mitochondrial damage and protected the neurons. These findings suggest that drugs or interventions to prevent damage to Drp1 could prove to be effective prevention or treatment strategies for Alzheimer’s disease.

Citation: Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA. S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science. 2009 Apr 3;324(5923):102-5.