Alzheimer’s Disease Mechanism Traced to Genetic Defect That Lowers Levels of a Mitochrondrial Protein

Researchers at two Norwegian institutions found that deficits in the mitochondrial protein PITRM1 led to an accumulation of amyloid-beta, whose deposits in the brain are known to cause Alzheimer’s disease. The findings, drawn from a study of a family with a rare genetic defect, further suggest that mitochondria is a key player in neurodegenerative diseases.

The study, “Defective PITRM1 mitochondrial peptidase is associated with Ab amyloidotic Neurodegeneration,” was published in the journal EMBO Molecular Medicine.

PITRM1 is located in the mitochondrial matrix, the extensive inner membrane of this cellular structure turning nutrients into energy. The protein functions to degrade protein fragments, and a homozygous mutation in the gene – affecting both gene copies – was seen to lead to a multitude of symptoms in an affected family.

Two siblings with the mutation suffered severe physical and psychological illness, including mental retardation, ataxia, cognitive decline, and psychosis. To study the consequences of the mutation in more detail, researchers from University of Bergen (UiB) and Haukeland University Hospital, Norway, induced mutations in cultured cells and studied a mouse lacking PITRM1. They observed that the mice had similar neurodegenerative characteristics as the patients, along with brain aggregates of amyloid-beta.

“The family had reduced amounts of this PITRM1 protein and became increasingly ill. Scans of their brains confirmed the damage, and when we tested mice with the same loss of PITRM1, these too had neurological problems and protein deposition in the brain,” researcher Janniche Torsvik at UiB’s Department of Clinical Medicine, said in a press release.

“When the level of PITRM1 in the cells decreases, this leads to an increase in the deposition of protein sediment in the brain,” Dr. Torsvik added.

In addition to understanding the specific genetic condition in the family, the study gives important clues about mechanisms leading to neurodegenerative diseases, such as Alzheimer’s. It is also one in a row of recent findings spotlighting the important role of mitochondria in neurodegenerative diseases.

“The results conclude a long discussion about the relationship between mitochondria and accumulation of amyloid in the brain. We have found that mitochondria play a crucial role in the process of protein deposition,” Dr. Torsvik said.

Professor Laurence A Bindoff, the study’s senior author, is eager to continue the research on PITRM1 and its role in neurodegenerative disease. “Our aim is that this research will help us find medications to prevent or delay diseases like Alzheimer’s,” he said.