Achilles’ heel identified in several neurodegenerative diseases

A Stanford research team has identified an oddball way brain cells spread inflammation in several neurodegenerative diseases — and an approach that could counter them all.

Many neurodegenerative diseases have a common feature that may make them amenable to the same treatment, investigators at the Stanford University School of Medicine have found.

“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, PhD, professor of chemical and systems biology at Stanford.

A paper describing the researchers’ findings was published today in Nature Neuroscience. Mochly-Rosen is the senior author. The lead author is postdoctoral scholar Amit Joshi, PhD.

Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis, or Lou Gehrig’s disease, share a common mode of damaging brain cells, the scientists learned in studying both human cells in culture and mouse models of the diseases. This damage can be blocked by administering a substance that inhibits a critical step in that process.

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.

Neuronal bits and fragments are perceived as foreign and targeted for clearance by microglia. But a vicious cycle of glial-cell activation and inflammation can occur in the absence of neuronal debris.

Mochly-Rosen, the George D. Smith Professor in Translational Medicine, and her colleagues discovered that mitochondria, essential components of cells, were conveying deleterious signals from microglia to astrocytes and from astrocytes to neurons. Mitochondria are tiny power packs: They furnish cells with energy. A typical nerve cell contains thousands of them. Their ability to communicate death signals from one cell to another was unexpected.

Convoluted tubular networks

Viewed close up, mitochondria are convoluted tubular networks that are perpetually being right-sized in a dynamic dance of fusion and fission, performed by opposing assemblies of enzymes. Mitochondria frequently get shuffled around from one part of a cell to another and must shift their shapes accordingly to accommodate their environments: Too much fusion, and they become too tubby to get around or work well. Too much fission, and they break up into dysfunctional fragments.

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 to amyotrophic lateral sclerosis. 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.


Source: Stanford Medicine

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