New Insights into Protein Accumulation in Alzheimer’s

Summary: Researchers have made an important discovery in understanding the mechanisms behind protein accumulation in neurodegenerative diseases such as Alzheimer’s disease. By studying fruit flies, the team discovered that a reduction in mitochondria in neuron axons directly leads to this harmful protein buildup.

They identified an increase in eIF2β protein as a critical factor; reducing its levels restored protein recycling and improved neuronal function. This breakthrough suggests a new target for therapies aimed at treating diseases like Alzheimer’s and ALS, potentially improving patient outcomes.

Highlights:

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

Source: Tokyo Metropolitan University

Researchers at Tokyo Metropolitan University have identified how proteins accumulate abnormally in neurons, a hallmark 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 elevated amounts of a protein called eIF2β were discovered. Restoring levels to normal allowed protein recycling to resume. Such discoveries promise new treatments against neurodegenerative diseases.

Every cell in our body is a working factory, where proteins are constantly being produced and disassembled. Any change or interruption in the production or recycling phases can result in serious illness. Neurodegenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis (ALS) are known to be accompanied by abnormal accumulation of proteins in neurons. However, the trigger for this accumulation remains unknown.

A team led by Associate Professor Kanae Ando of Tokyo Metropolitan University attempted to determine the causes of abnormal protein accumulation 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 extend from neurons and form the necessary connections that allow signals to be transmitted inside our brains. It is known that mitochondrial levels in axons can drop with age and during the progression of neurodegenerative diseases.

Now the team has discovered that the decrease in mitochondria in axons has a direct impact on protein accumulation. They used genetic modification to suppress the production of Milton, a key protein in transporting mitochondria along axons.

This was found to lead to abnormal protein accumulation in fruit fly neurons, a result of the breakdown of autophagy, the recycling of proteins within cells. Through proteomic analysis, they were able to identify significant upregulation of eIF2β, a key subunit of the eIF2 protein complex responsible for initiating protein production (or translation).

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

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

As populations age and the prevalence of neurodegenerative diseases continues to increase, the team’s findings represent a critical step in developing therapies to combat these serious diseases.

Funding: This work was supported by a Sasakawa Scientific Research Grant (2021-4087), the Takeda Science Foundation, a grant from the Hoansha Foundation, a research grant from the Japan Foundation for Aging and Health, and the Novartis Foundation ( Japan) for the Promotion of Science, a Grant-in-Aid for Scientific Research on Difficult (Exploratory) Research (JSPS KAKENHI grant number 19K21593), NIG-JOINT (National Institute of Genetics, 71A2018, 25A2019) and the Fund of strategic research TMU for social engagement.

About this neurology research news

Author: GO TO TOTSUKAWA
Source: Tokyo Metropolitan University
Contact: GO TOTSUKAWA – Tokyo Metropolitan University
Picture: Image is credited to Neuroscience News

Original research: Free access.
“Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β” by Kanae Ando et al. eLife

Abstract

Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β

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

Impaired mitochondrial transport in the axon is another hallmark of aging and neurodegenerative diseases. Using Drosophilawe found that genetic depletion of axonal mitochondria causes translational dysregulation and protein degradation.

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

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

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

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