Protein overload causes anarchy

RUTGERS (US) — Too much of a key protein in the brain can lead to a revolt, thwarting the normal growth of neurons and potentially leading to cognitive disorders.

Details of a new study are published in the Journal of Neuroscience.

PSD-95 is necessary for the growth of dendrites, the parts of neurons that reach out to, and help connect with, other cells.

To understand what’s going on in the neurons in our brains, start by looking at your hand, says lead author Bonnie Firestein, professor of cell biology and neuroscience at Rutgers. Imagine the center of your hand is the body of a neuron—a nerve cell—and the fingers are dendrites.

Dendrites reach almost, but not quite, to other neurons, separated from them by a tiny space called a synapse. The two cells on either side of a synapse use that space to send electrical and chemical signals to each other.

The reaching out of neurons to other cells—and therefore, the ability of neurons to reach out at all—is essential to the functioning of the nervous system. Anything that interferes with that reaching out might lead to cognitive disorders, such as autism, Firestein says.

“If your hand is a cell and your fingers are dendrites, how would you add another finger? You’d have to add bones and flesh, and what’s the cellular equivalent?”

The cellular equivalents, Firestein says, are tiny, hollow structures called microtubules which, when a new dendrite is formed, line up in the right way to support the new structure.

In a microscopic image, they look like a raft of freshly cut logs floating down a river. The protein PSD-95 has to be present in just the right amount for that to happen.

But too much PSD-95 causes microtubule anarchy. The microtubules, instead of floating straight down the new structure to support it, turn back on themselves, twist themselves into odd shapes, and generally fail to do their job.

PSD-95 interacts with EB3, another protein located on the end of microtubules that serves as a binder. If the PSD-95 is “overexpressed”—that is, if there is too much of it—or if the EB3 is mutated, then the microtubules don’t line up as they should, and the physical structure of the dendrite is changed.

Change may be the law of life, but this is one of those cases where any change is bad, Firestein says. Anything the microtubules do other than line up properly can only lead to trouble.

“We think this is a basic mechanism, and if you alter the amount of PSD 95 in a cell, you’ll alter the way the dendrites form,” she says. “And if you do that, you can end up with cognitive disorders like autism.”

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