Presenilin mutations deregulate mitochondrial Ca

Mitochondrial dysfunction and subsequent metabolic deregulation is observed in neurodegenerative diseases and aging. Mutations in the presenilin (PSEN) encoding genes (PSEN1 and PSEN2) cause most cases of familial Alzheimer’s disease (AD); however, the underlying mechanism of pathogenesis remains unclear. Here, we show that mutations in the C. elegans gene encoding a PSEN homolog, sel-12 result in mitochondrial metabolic defects that promote neurodegeneration as a result of oxidative stress. In sel-12 mutants, elevated endoplasmic reticulum (ER)-mitochondrial Ca2+ signaling leads to an increase in mitochondrial Ca2+ content which stimulates mitochondrial respiration resulting in an increase in mitochondrial superoxide production. By reducing ER Ca2+ release, mitochondrial Ca2+ uptake or mitochondrial superoxides in sel-12 mutants, we demonstrate rescue of the mitochondrial metabolic defects and prevent neurodegeneration. These data suggest that mutations in PSEN alter mitochondrial metabolic function via ER to mitochondrial Ca2+ signaling and provide insight for alternative targets for treating neurodegenerative diseases.
eLife digest Alzheimer's disease is the most common type of dementia. A hallmark of this condition is progressive loss of memory, accompanied by a buildup of hard clumps of protein between the brain cells. These protein clumps, known as amyloid plaques, are a key focus of research into Alzheimer's disease. They are likely to be toxic to brain cells, but their role in the development and progression of the disease is not yet known. Though the cause of Alzheimer's disease remains unclear, an inherited form of the disease may hold some clues. Mutations in genes for proteins called presenilins cause an earlier onset form of Alzheimer's disease, in which symptoms can develop in people who are in their 40s or 50s. The presenilin proteins appear in a cell structure called the endoplasmic reticulum, which plays many roles in the normal activities of a cell. Among other things, this structure stores and releases calcium ions, and cells use these ions to send and process many signals. The cell's energy-producing powerhouses, the mitochondria, use calcium to boost their metabolic activity. This allows them to make more energy for the cell, but in the process they also make damaging byproducts. These byproducts include oxygen-containing chemicals, known as reactive oxygen species (ROS), which react strongly with other molecules. While low levels of ROS are a normal part of cell activity, if the levels get too high, these chemicals can attack and damage structures within the cell. Untangling the effects of amyloid plaques and presenilins on brain cells in humans is challenging. But, a nematode worm called Caenorhabditis elegans does not form plaques, making it possible to look at presenilins on their own. Previous work in these worms has shown that presenilin mutations affect the endoplasmic reticulum and change the appearance of mitochondria. Here, Sarasija et al. extend this work to find out more about the effects presenilin mutations have on living cells. Presenilin mutations in young adult worms increased the amount of calcium released by the endoplasmic reticulum. This increased the activity of the mitochondria and caused ROS levels to rise to damaging levels. This caused stress inside the cells, and the worms started to show early signs damage to their nervous systems. Mutations that decreased the movement of calcium from the endoplasmic reticulum to the mitochondria helped to prevent the damage. Treating the mitochondria with antioxidants to mop up the extra ROS also protected the cells. This kind of damage to brain cells did not depend on amyloid plaques. Whilst the plaques are likely to be toxic, these new findings highlights the role that other chemical and biological processes might play in Alzheimer's disease. Further work to reveal the underlying cause of Alzheimer's disease may lead to new therapies to treat this condition in the future.