In neurodegenerative diseases such as Alzheimer's and Parkinson's,
naturally-occurring proteins fold into the wrong shape and clump
together into filament-like structures known as amyloid fibrils and
smaller, highly toxic clusters known as oligomers which are thought to
damage or kill neurons, however the exact mechanism remains unknown.
For the past two decades, researchers have been attempting to
develop treatments which stop the proliferation of these clusters in the
brain, but before any such treatment can be developed, there first
needs to be a precise understanding of how oligomers form and why.
‘New super-resolution techniques have allowed researchers to study why proteins associated with Alzheimer's and Parkinson's diseases may go from harmless to toxic.’
Researchers have developed a new imaging technique that makes it
possible to study why proteins associated with Alzheimer's and
Parkinson's diseases may go from harmless to toxic. The technique uses a
technology called multi-dimensional super-resolution imaging that makes
it possible to observe changes in the surfaces of individual protein
molecules as they clump together. The tool may allow researchers to
pinpoint how proteins misfold and eventually become toxic to nerve cells
in the brain, which could aid in the development of treatments for
these devastating diseases.
The researchers, from the University of Cambridge, have studied how a
phenomenon called hydrophobicity (lack of affinity for water) in the
proteins amyloid-beta and alpha synuclein - which are associated with
Alzheimer's and Parkinson's respectively - changes as they stick
together. It had been hypothesized that there was a link between the
hydrophobicity and toxicity of these proteins, but this is the first
time it has been possible to image hydrophobicity at such high
resolution. Details are reported in the journal Nature Communications
"These proteins start out in a relatively harmless form, but when
they clump together, something important changes," said Dr. Steven Lee
from Cambridge's Department of Chemistry, the study's senior author.
"But using conventional imaging techniques, it hasn't been possible to
see what's going on at the molecular level."
"There's something special about oligomers, and we want to know what
it is," said Lee. "We've developed new tools that will help us answer
When using conventional microscopy techniques, physics makes it
impossible to zoom in past a certain point. Essentially, there is an
innate blurriness to light, so anything below a certain size will appear
as a blurry blob when viewed through an optical microscope, simply
because light waves spread when they are focused on such a tiny spot.
Amyloid fibrils and oligomers are smaller than this limit so it's very
difficult to directly visualise what is going on.
However, new super-resolution techniques, which are 10 to 20 times
better than optical microscopes, have allowed researchers to get around
these limitations and view biological and chemical processes at the
Lee and his colleagues have taken super-resolution techniques one
step further, and are now able to not only determine the location of a
molecule, but also the environmental properties of single molecules
Using their technique, known as sPAINT (spectrally-resolved points
accumulation for imaging in nanoscale topography), the researchers used a
dye molecule to map the hydrophobicity of amyloid fibrils and oligomers
implicated in neurodegenerative diseases. The sPAINT technique is easy
to implement, only requiring the addition of a single transmission
diffraction gradient onto a super-resolution microscope. According to
the researchers, the ability to map hydrophobicity at the nanoscale
could be used to understand other biological processes in future.