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Drug Target Could Fight Parkinson’s and Alzheimer’s Disease | Nutrition Fit


Summary: The SARM1 protein triggers a cascade of degeneration associated with Alzheimer’s, Parkinson’s, and other neurodegenerative diseases. Researchers hope new drugs can be developed to directly target this protein to fight neurodegeneration.

Source: University of Queensland

Neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease are in the firing line after researchers identified an attractive therapeutic drug target.

An international collaboration, co-led by University of Queensland researchers, has isolated and analysed the structure and function of a protein found in the brain’s nerve fibres called SARM1.

Dr Jeff Nanson said the protein was activated when nerve fibres were damaged by injury, disease, or as a side effect of certain drugs.

“After a damaging incident occurs, this protein often induces a form of nerve fibre degeneration – known as axon degeneration – a ‘self-destruct’ mechanism of sorts,” Dr Nanson said.

“This is a key pathological feature of many terrible neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease, and also amyotrophic lateral sclerosis (ALS), traumatic brain injury, and glaucoma.

“There are currently no treatments to prevent this nerve fibre degeneration, but now we know that SARM1 is triggering a cascade of degeneration we can develop future drugs to precisely target this protein.

“This work will hopefully help design new inhibiting drugs that could stop this process in its tracks.”

Professor Bostjan Kobe said the researchers analysed the structure of the protein and defined its three-dimensional shape using X-ray crystallography and cryo-electron microscopy.

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“With X-ray crystallography, we make proteins grow into crystals, and then shoot X-rays at the crystals to get diffraction,” Professor Kobe said.

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This shows a brain made up of SARM1
An artist’s impression of the brain, made from images of the SARM1 protein. Credit: University of Queensland

“And with cryo-electron microscopy, we freeze small layers of solution and then visualise protein particles by a beam of electrons.

“The resulting 3D images of SARM1’s ring-like structure were simply beautiful, and truly allowed us to investigate its purpose and function.

“This visualisation was a highly collaborative effort, working closely with our partners at Griffith University and our industry partners.”

The researchers hope that the discovery is the start of a revolution in treatments for neurodegenerative disorders.

“It’s time we had effective treatments for these devastating disorders,” Dr Nanson said.

“We know that these types of diseases are strongly related to age, so in the context of an ageing population here in Australia and globally, these diseases are likely to increase.

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“It’s incredibly important that we understand how they work and develop effective treatments.”

About this neurology research news

Source: University of Queensland
Contact: Bostjan Kobe – University of Queensland
Image: The image is credited to University of Queensland

Original Research: Closed access.
SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration” by Bostjan Kobe et al. Neuron


Abstract

SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration

Highlights

  • SARM1 is activated by an increase in the ratio of NMN to NAD +
  • NMN and NAD + compete for binding to the auto-inhibitory ARM domain of SARM1
  • NMN binding influences the structure of SARM1
  • NMN binding is required for injury-induced SARM1 activation and axon destruction
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Summary

Axon degeneration is a central pathological feature of many neurodegenerative diseases. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD +)-cleaving enzyme whose activation triggers axon destruction. Loss of the biosynthetic enzyme NMNAT2, which converts nicotinamide mononucleotide (NMN) to NAD +, activates SARM1 via an unknown mechanism.

Using structural, biochemical, biophysical, and cellular assays, we demonstrate that SARM1 is activated by an increase in the ratio of NMN to NAD + and show that both metabolites compete for binding to the auto-inhibitory N-terminal armadillo repeat (ARM) domain of SARM1. We report structures of the SARM1 ARM domain bound to NMN and of the homo-octameric SARM1 complex in the absence of ligands.

We show that NMN influences the structure of SARM1 and demonstrate via mutagenesis that NMN binding is required for injury-induced SARM1 activation and axon destruction. Hence, SARM1 is a metabolic sensor responding to an increased NMN/NAD + ratio by cleaving residual NAD +, thereby inducing feedforward metabolic catastrophe and axonal demise.



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