Jumping Mitochondrial Genes May Contribute To Alzheimer’s

Posted on 9 March 2017

Unstable genetic elements in mitochondria may become ‘uncaged’ in Alzheimer’s disease

With researchers floundering in Alzheimer’s research as many promising drugs continue to fail, some are forming new theories about what might drive the disease. One of these revolves around dysfunctional mitochondria.  A new hypothesis Researchers at Duke University have formed a new hypothesis called the ‘Alu Neurodegeneration Hypothesis’, which proposes that control over short, jumping genetic elements called Alus is loosened during aging; leaving them to wreak havoc on mitochondria and drive Alzheimer’s disease. 

“Alu elements are a double-edged sword. Once dismissed as selfish or junk DNA, they are now recognized as contributors to the diversity and complexity of the human brain. “They can provide new and beneficial gene functions. They have helped humans evolve higher cognitive function, but perhaps at the cost of neuron vulnerability that increases with age”

3-D modeling of the TOMM40 gene Credit: Peter Larsen

3-D modeling of the TOMM40 gene Credit: Peter Larsen

Previous research discovered that the length of a particular mitochondrial gene called TOMM40 was correlated with Alzheimer’s risk. On closer analysis it was revealed that this section is packed with these Alu sequences, which are a member of the retrotransposon family. These rogue sequences play an important evolutionary role, but they’re also risky as they have a tendency to integrate within and disrupt other genes. Usually these Alu sequences are controlled by methyl groups which silences their activity, but researchers theorise that loss of control of this regulation (as is known to happen with age) may unleash their chaotic activity.  When the team constructed a 3D model of TOMM40 protein, which forms a gateway for amyloid beta to enter mitochondria, they found that Alu insertions within the TOMM40 sequence could compromise the structure. This blocked up the gateway and conceivably prevents the import of proteins into the mitochondria. 

“We need to start thinking outside of the box when it comes to treating neurological diseases like Alzheimer’s”

While at this point the theory is far from proven, it raises some new interesting questions and may represent a new drug target too. It’s looking increasingly likely that Alzheimer’s is a complex disease with multiple contributing factors, so placing all our eggs in one basket may be a foolish approach. Attempting to deal with microbial burden, inflammation, mitochondrial dysfunction and microglial rejuvenation all at once for example could be something to watch for in the future. The importance of treating the disease early has also been underlined recently, so it may be that medical approaches applied in early stage and late stage Alzheimer’s patients may have very different effects.  Read more at MedicalXpress

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