Researchers get a lead on how to detect degenerative neurological diseases sooner

September 29, 2017, The Scripps Research Institute
TSRI postdoctoral researcher Joseph D. Schonhoft and graduate student Cecilia Monteiro. Credit: TSRI

Researchers at The Scripps Research Institute (TSRI) may have found a way to help doctors diagnose diseases like Alzheimer's and Parkinson's earlier in their progression. A special peptide probe being developed in Jeffery Kelly's lab at TSRI is showing promise as a tool for detecting the early signs of transthyretin (TTR) polyneuropathy, a progressive neurological disease. This probe could enable doctors to implement interventions before degeneration becomes too severe, allowing treatments to be more effective. This probe may also increase our understanding regarding which aggregate structure(s) disrupts the normal functions of neurons.

Misfolded proteins misassemble into amyloid in a defined insoluble 3D structure. Since are a common feature of most neurodegenerative diseases, this structure is considered responsible for a variety of , from cardiomyopathies to neurodegenerative diseases including Alzheimer's, without much direct evidence. Recent evidence suggests that soluble oligomeric aggregates rather than amyloid may, in fact, be the culprit.

This TSRI study, focused on making peptide probes for aggregates other than , was conducted by postdoctoral researcher Joseph D. Schonhoft and graduate student Cecilia Monteiro. Prior to joining the Kelly Lab as a graduate student, Monteiro was a practicing neurologist in Portugal, where she treated neurodegenerative disease patients, including TTR amyloid polyneuropathy patients. The TTR amyloidoses are amyloid diseases where misfolded TTR assemblies cause neurodegeneration or cardiomyopathy, depending on the sequence of TTR that aggregates.

"Cecilia is a physician scientist and came to TSRI with a clinical background, and I am a biophysicist and biochemist. Together we formed a unique interdisciplinary team for this research," said Schonhoft.

Some diagnostic strategies detect insoluble amyloids using antibodies designed to bind to them and make them visible to scientists. But before amyloid develops, the body may produce soluble misfolded oligomeric aggregates in a non-amyloid conformation. The TSRI team developed a peptide-based probe that can detect non-native TTR oligomers earlier in the disease progression, before amyloid is easily detected (the probe does not recognize amyloid).

The researchers used their peptide probe to detect non-native TTR oligomers in the plasma of a group of patients diagnosed with TTR polyneuropathy, alongside samples from a healthy control group and asymptomatic carriers of the mutation that causes the majority of TTR polyneuropathy cases. The study revealed that patients with the disease had higher levels of non-native TTR oligomers than either of the two control groups. In addition, a subset of patients who had been treated for the disease with the drug tafamidis (discovered by the Kelly Lab and sold by Pfizer), as well as liver transplant-mediated gene therapy showed lower levels of non-native TTR oligomers. These results demonstrate proof of concept for using the peptide probe for early diagnosis and as a response to therapy biomarker.

The researchers are now scrutinizing the utility of their peptide in larger numbers of patients in order to correlate the levels of the non-native TTR oligomers with disease initiation and progression. Little is known about which aggregate structure causes these degenerative diseases.

"One of the biggest questions in the field is whether the soluble oligomers are a driver of disease. Our approach may be able to answer that question," said Monteiro.

Explore further: Protein research could help in hunt for Alzheimer's and Parkinson's cures

Related Stories

Protein research could help in hunt for Alzheimer's and Parkinson's cures

September 11, 2017
Research carried out at the University of Kent has the potential to influence the future search for treatment of neurodegenerative diseases that are linked to a family of protein molecules known as 'amyloid'.

Fighting Alzheimer's disease with protein origami

July 12, 2013
Alzheimer's disease is a progressive degenerative brain disease most commonly characterized by memory deficits. Loss of memory function, in particular, is known to be caused by neuronal damage arising from the misfolding ...

A human enzyme can reduce neurotoxic amyloids in a mouse model of dementia

June 27, 2017
A naturally occurring human enzyme -called cyclophilin 40 or CyP40- can unravel protein aggregates that contribute to both Alzheimer's disease and Parkinson's disease, according to a study publishing June 27 in the open access ...

Peptide complex in the brain is responsible for Alzheimer's disease

July 17, 2017
Members of the Faculty of Fundamental Medicine at the Lomonosov Moscow State University have determined the structure of a peptide complex formed in the brain at the early stages of Alzheimer's disease. The research results ...

Researchers investigate the amyloid-beta peptide behind Alzheimer's

November 5, 2012
Using solid-state nuclear magnetic resonance (NMR) spectroscopy, researchers at Luleå University of Technology in collaboration with Warwick University in the UK for the first time in the world managed to analyse hydrogen ...

Recommended for you

How the brain makes rapid, fine adjustments in motor activity

October 18, 2018
Short-term motor learning appears not to require physical change in the brain Brain's premotor cortex may use a 'neural scratch pad' to calculate fine adjustments Brain can try different things in simulation without 'screwing ...

Scientists uncover how rare gene mutation affects brain development and memory

October 18, 2018
Researchers from the University of California, Irvine School of Medicine, have found that a rare gene mutation alters brain development in mice, impairing memory and disrupting the communication between nerve cells. They ...

Weight loss success linked with active self-control regions of the brain

October 18, 2018
New research suggests that higher-level brain functions have a major role in losing weight. In a study among 24 participants at a weight-loss clinic, those who achieved greatest success in terms of weight loss demonstrated ...

Electrical properties of dendrites help explain our brain's unique computing power

October 18, 2018
Neurons in the human brain receive electrical signals from thousands of other cells, and long neural extensions called dendrites play a critical role in incorporating all of that information so the cells can respond appropriately.

Brain cells called astrocytes have unexpected role in brain 'plasticity'

October 18, 2018
When we're born, our brains have a great deal of flexibility. Having this flexibility to grow and change gives the immature brain the ability to adapt to new experiences and organize its interconnecting web of neural circuits. ...

Study pinpoints what makes human neurons unique

October 18, 2018
Human neurons are much larger than those of model organisms mice and rats, so it's been unclear whether it's size that makes a difference in our brain's computational power. Now, in a study appearing October 18 in the journal ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.