Fruit flies are helping researchers decipher the genetic link to Alzheimer’s disease

summary: The findings reveal a possible cause of neurodegeneration in the early stages of Alzheimer’s disease.

Source: Walter and Eliza Hall Institute

Researchers used fruit flies to decipher the unexplained link between Alzheimer’s disease and genetic variation, revealing that it causes nerve cells to die.

The findings from the Walter and Elisa Hall Institute (WEHI) team reveal a possible cause of neurodegeneration in the early stages of Alzheimer’s disease, and open the door to the development of new treatments for cognitive diseases in the future.

The study, “Increase in mitochondrial TOM activates apoptosis to drive retinal neurodegeneration,” in collaboration with collaborators from the Australian National University, is published in Scientific reports.

It is believed that more than 55 million people worldwide are living with Alzheimer’s disease or other forms of dementia. In Australia, there are as many as 487,500 people living with dementia. There is no known cure for this disease, but early intervention can help prevent the disease from progressing.

The new research advances our knowledge of how cell death and quality control pathways are involved in neurodegeneration and reveals potential targets for early intervention in cognitive states.

A gap in dementia research

There is a strong genetic association between increased levels of the mitochondrial gene TOMM40 and Alzheimer’s disease, but the mechanisms underlying this phenomenon are largely unknown.

This link was difficult to decipher because this gene neighbors the ‘Alzheimer’s gene’ (ApoE), the strongest predictor of late-onset Alzheimer’s disease. But recent work has shown a genetic variation that causes overproduction of TOMM40 can cause brain shrinkage, regardless of the Alzheimer’s gene.

Lead researcher Dr. Aghalia Periyasamy said the findings intrigued the team, leading them to investigate the extent to which TOMM40 causes neurodegeneration underlying Alzheimer’s disease.

“If we can untangle this, we may be able to find a new way to intervene in the process to prevent neurons from dying,” said Dr. Periyasamy.

“Currently, we do not have good treatments for Alzheimer’s disease and we urgently need new options. Our research offers a potential alternative avenue for developing much-needed therapeutic interventions for this devastating disease.”

fruit fly model

The WEHI and Australian National University team used a popular neurodegenerative disease model, the fruit fly, to explore potential links between elevated TOMM40 levels and Alzheimer’s disease. The eyes of fruit flies contain cells called photoreceptors that are specialized nerve cells, making them ideal for looking for neurodegeneration.

To investigate how an overexpression of TOMM40 might be associated with neurodegeneration, the team genetically engineered fruit flies to produce too much Tom40, the protein produced by the TOMM40 gene, and observed the effect.

They found that enrichment of the protein caused significant cell death in the retina, with an amount of degeneration corresponding to the level of the protein.

After researching why eye tissue was dying, Dr. Periyasamy found evidence of a specific type of cell death called apoptosis, which is normally involved in regular cell turnover and maintenance.

This shows neurons
Eye of a fly larva under a microscope – the specialized neurons inside it were made to overexpress the Tom40 protein that glows red. Credit: Agalya Periasamy/WEHI

“We looked at the eyes of larvae of flies under a microscope and found an increase in a protein that signals the activation of apoptosis, called ‘caspase-3’ in humans. This confirmed to us that apoptosis was the missing link we were looking for.”

TOM protein complex and cell death

Tom40 is part of a larger protein complex called ‘TOM’ that assembles in mitochondria, where its main function is to import essential proteins.

The team investigated the effect of Tom40 overexpression and found that TOM complex formation was sent into overdrive. This throws homeostasis in the mitochondria and activates apoptosis.

“While the data shows that cell death is caused by an overabundance of the TOM population, we found no evidence that protein import was involved in neurodegeneration,” said lead researcher Dr. Jackie Gulbis. Our findings identify a new entry point into cell quality control pathways that can be targeted to interrupt TOMM40-induced neurodegeneration.

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“While this research is still in its early stages, it will be exciting to explore the relationship between TOMM40-associated apoptosis and Alzheimer’s disease and benefit from it to lay the groundwork for developing new therapies for cognitive conditions.”

About this genetics and Alzheimer’s disease research news

author: press office
Source: Walter and Eliza Hall Institute
Contact: Press Office – Walter and Eliza Hall Institute
picture: Image credit: Agalya Periasamy/WEHI

Original search: open access.
An increase in TOM in mitochondria activates apoptosis to drive retinal neurodegenerationBy Agalya Periasamy et al. Scientific reports


An increase in TOM in mitochondria activates apoptosis to drive retinal neurodegeneration

Polymorphic Intronic Tom 40 incremental variables Tom 40 mRNA expression is closely associated with late-onset Alzheimer’s disease. Gene product, hTomm40, encoded in file APOE The gene cluster, is an essential component of the TOM, which are transcases that import nascent proteins across the outer mitochondrial membrane.

We were Drosophila melanogaster Eyes as an in vivo model to investigate the relationship between elevated Tom40 ( Drosophila homologue of hTomm40) expression and neurodegeneration.

Here we provide evidence that an overexpression of Tom40 in mitochondria induces caspase-dependent cell death in a dose-dependent manner, leading to degeneration of primarily ocular neuronal tissues.

Degeneration hinges on the availability of co-assembled TOM components, suggesting that an increase in aggregated TOM is the factor leading to apoptosis and degeneration in a neuronal setting. Eye death is not dependent on endomembrane envelope components, indicating that it is unlikely to be a direct result of impaired import.

Another effect of increased Tom40 expression is the co-upregulation and association of a biomarker of mitochondrial oxidative stress, DrHsp22, which is implicated in life extension, providing new insight into the balance between cell survival and cell death.

Activation of regulated death pathways, culminating in ocular degeneration, suggests a possible causal pathway Tom 40 Polymorphisms of neurodegenerative disease.

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