Protein accumulation

New Insights into Protein Accumulation in Alzheimer’s

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Summary: Researchers made a significant discovery in understanding the mechanisms behind protein accumulation in neurodegenerative diseases like Alzheimer’s. By studying fruit flies, the team found that a reduction in mitochondria within neuron axons leads directly to this detrimental protein buildup.

They pinpointed a rise in the protein eIF2β as a critical factor; reducing its levels restored protein recycling and improved neuron function. This breakthrough suggests a new target for therapies aimed at treating conditions like Alzheimer’s and ALS, potentially improving outcomes for patients.

Key Facts:

  1. The study revealed that depletion of mitochondria in neuron axons causes abnormal protein accumulation, a hallmark of diseases like Alzheimer’s.
  2. Researchers identified an increase in the protein eIF2β as a key contributor to this process; adjusting its levels could reverse the effects.
  3. The findings, derived from genetic studies in fruit flies, open the door to developing new treatments that could target mitochondrial health or regulate protein levels to combat neurodegenerative diseases.

Source: Tokyo Metropolitan University

Researchers from Tokyo Metropolitan University have identified how proteins collect abnormally in neurons, a feature of neurodegenerative diseases like Alzheimer’s. They used fruit flies to show that depletion of mitochondria in axons can directly lead to protein accumulation.

At the same time, significantly high amounts of a protein called eIF2β were found. Restoring the levels to normal led to a recovery in protein recycling. Such findings promise new treatments for neurodegenerative diseases.

This shows neurons.
It is known that the levels of mitochondria in axons can drop with age, and during the progress of neurodegenerative diseases.

Every cell in our bodies is a busy factory, where proteins are constantly being produced and disassembled. Any changes or lapses in either the production or recycling phases can lead to serious illnesses. Neurodegenerative diseases such as Alzheimer’s and Amyotrophic Lateral Sclerosis (ALS), for example, are known to be accompanied by an abnormal build-up of proteins in neurons. However, the trigger behind this accumulation remains unknown.

A team led by Associate Professor Kanae Ando of Tokyo Metropolitan University have been trying to determine the causes of abnormal protein build-up by studying Drosophila fruit flies, a commonly studied model organism that has many key similarities with human physiology.

They focused on the presence of mitochondria in axons, the long tendril-like appendages that stretch out of neurons and form the necessary connections that allow signals to be transmitted inside our brains. It is known that the levels of mitochondria in axons can drop with age, and during the progress of neurodegenerative diseases.

Now, the team have discovered that the depletion of mitochondria in axons has a direct bearing on protein build-up. They used genetic modification to suppress the production of milton, a key protein in the transport of mitochondria along axons.

It was found that this led to abnormal levels of protein building up in fruit fly neurons, a result of the breakdown of autophagy, the recycling of proteins in cells. Through proteomic analysis, they were able to identify a significant upregulation in eIF2β, a key subunit of the eIF2 protein complex responsible for the initiation of protein production (or translation).

The eIF2α subunit was also found to be chemically modified. Both of these issues hamper the healthy action of eIF2.

Importantly, by artificially suppressing levels of eIF2β, the team discovered that they could restore the autophagy that was lost and regain some of the neuron function that was impaired due to axonal mitochondria loss. This not only shows that depletion of mitochondria in axons can cause abnormal protein accumulation, but that this happens via upregulation of eIF2β.

As populations age and the prevalence of neurodegenerative conditions continues to increase, the team’s findings present a vital step in developing therapies to combat these serious illnesses.

Abstract

Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β

Neuronal aging and neurodegenerative diseases are accompanied by proteostasis collapse, while cellular factors that trigger it are not identified.

Impaired mitochondrial transport in the axon is another feature of aging and neurodegenerative diseases. Using Drosophila, we found that genetic depletion of axonal mitochondria causes dysregulation of translation and protein degradation.

Axons with mitochondrial depletion showed abnormal protein accumulation, and autophagic defects. Lowering neuronal ATP levels by blocking glycolysis did not reduce autophagy, suggesting that autophagic defects are associated with mitochondrial distribution.

We found eIF2β was upregulated by depletion of axonal mitochondria via proteome analysis. Phosphorylation of eIF2α, another subunit of eIF2, was lowered, and global translation was suppressed.

Neuronal overexpression of eIF2β phenocopied the autophagic defects and neuronal dysfunctions, and lowering eIF2β expression rescued those perturbations caused by depletion of axonal mitochondria.

These results indicate the mitochondria-eIF2β axis maintains proteostasis in the axon, of which disruption may underly the onset and progression of age-related neurodegenerative diseases.

Protein accumulation on fat droplets implicated in late-onset Alzheimer’s disease

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brain

UNC School of Medicine researcher Sarah Cohen, Ph.D., and Ian Windham, a former Ph.D. student from the Cohen lab, have made a new discovery about apolipoprotein E (APOE)—the biggest genetic risk factor for late-onset Alzheimer’s disease.

Older people who inherited a genetic variant called APOE4 from their parents have a two- or three-times greater risk of developing late-onset neurodegenerative disease. If researchers can better understand how APOE4 affects brain cells, it may help them design effective therapeutics and target the mechanisms causing the enhanced disease risk.

Cohen and Windham performed an exceptionally thorough, five-year-long study to understand better and visualize the relationship between APOE4, Alzheimer’s Disease, and fat molecules called lipids in the brain.

“We discovered that brain cells known as astrocytes are more vulnerable to damage and may even go dysfunctional when APOE4 surrounds their lipid storage centers,” said Cohen, assistant professor of cell biology and physiology and senior author on the paper published in the Journal of Cell Biology. “This mechanism could explain why exactly APOE4 increases one’s risk of Alzheimer’s on the cellular level.”

The role of lipids in the brain

Sixty percent of the brain’s dry mass is composed of lipids, which play important roles in the brain, such as storing cellular energy and forming myelin, which surrounds and insulates neurons. Lipids can be found in specialized fat storage compartments known as lipid droplets within astrocytes.

As helpful as they may be, lipids can also become toxic if the conditions are right. When excited or stressed, neurons release toxic lipids into the environment. Astrocytes are tasked with cleaning up the free-floating toxic lipids and preventing them from accumulating in the brain.

If astrocytes were to become damaged or dysfunctional in any way, they cannot perform their cleaning duties. As a result, other brain cells, called microglia, cannot clean up amyloid beta plaques in the brain either, another driving factor for Alzheimer’s disease.

Seeing APOE in real-time

APOE is produced by astrocytes. Much like a taxi or Uber, the protein oversees the release and transport of lipids between cell types in the brain. Windham and Cohen wanted to see what exactly happens with the lipids in the astrocytes. Windham led the charge, creating a labeling and tagging system that would allow them to see the innards of astrocytes in action under the microscope.

“Tagging APOE with green fluorescent protein allowed us to see the different places APOE goes while inside living cells,” said Windham, now a postdoctoral fellow at The Rockefeller University and first author on the paper.

The team first fed astrocytes oleic acid, an omega-9 fatty acid naturally produced in the body. Using a microscope, the team observed the usual formation of lipid droplets. APOE4, surprisingly, zipped over to the lipid droplets like a magnet and changed the shape and size of the droplets.

It became abundantly clear to the researchers that APOE4 can escape secretion, lock itself inside astrocytes, and migrate to lipid droplets within astrocytes. Windham and Cohen hypothesize that the altered composition of the lipid droplets could be causing astrocyte dysfunction and affecting the microglia’s ability to clear amyloid beta.

Lipids: The next frontier

However, more research needs to be done to know the specifics. Cohen hopes their findings will further emphasize the role of lipid droplets in Alzheimer’s disease and other neurodegenerative diseases.

“In Alois Alzheimer’s first paper, he described three characteristics of neurodegenerative disease: amyloid beta plaques, tau tangles, and accumulations of lipids,” said Cohen. “The first two have gotten a lot of attention. The next frontier is lipids. With APOE being the biggest genetic risk factor, we think it holds the clues for how lipids fit into the story.”