Researchers at Stanford Discover Common Denominator In Several Neurodegenerative Diseases

Investigators at the Stanford University School of Medicine have found, in both mouse brain models and human brain cultures, that Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, or Lou Gehrig’s disease, share a common mode of damaging brain cells.

 “We’ve identified a potential new way to reduce nerve-cell death in a number of diseases characterized by such losses,” said Daria Mochly-Rosen, Ph.D., professor of chemical and systems biology at Stanford.

A paper describing the researchers’ findings was published on September 23rd in Nature Neuroscience. Mochly-Rosen is the senior author. The lead author is postdoctoral scholar Amit Joshi, Ph.D.

The new study implicates two types of normally protective brain cells called glial cells in tripping off neuronal destruction: Microglia monitor the brain for potential trouble — say, signs of tissue injury or the presence of invading microbial pathogens — and scavenge debris left behind by dying cells or protein aggregates. Astrocytes, which outnumber the brain’s neurons nearly 5 to 1, release growth factors, provide essential metabolites and determine the number and placement of the connections neurons make with one another. Mitochondria released by inflamed microglia and astrocytes were more apt to be damaged. When expelled mitochondria are in bad shape, it’s lethal for nearby neurons. 

An enzyme called Drp1 that facilitates mitochondrial fission can be catapulted into hyperactivity by neurotoxic protein aggregates such as those linked to Alzheimer’s, Parkinson’s or Huntington’s diseases or amyotrophic lateral sclerosis (ALS). About seven years ago, Mochly-Rosen’s team designed a tiny protein snippet, or peptide, called P110, that specifically blocks Drp1-induced mitochondrial fission when it’s proceeding at an excessive pace, as happens when a cell is damaged. 

The study showed that sustained P110 treatment via a subcutaneous pump over periods of several months lowered the microglial and astrocytic activation and inflammation in the brains of mice. 

How do expelled mitochondria that are damaged produce inflammation and neuronal cell death? “We’re working hard to find that out,” she said.

Joshi and Mochly-Rosen have filed for a patent on P110 and its utility in Huntington’s disease, ALS and other neurodegenerative diseases.

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