Nearly one million people in the United States are living with Parkinson's disease (PD). Parkinson's disease and other "synucleinopathies" are known to
be linked to the misfolding of alpha-synuclein protein in neurons.
clear is how this misfolding relates to the growing number of genes
implicated in PD through analysis of human genetics.
‘A suite of novel biological and computational methods were used to shed light on how protein misfolding relates to the growing number of genes implicated in Parkinson's Disease.’
In two studies
published in the advance online edition of Cell Systems
researchers affiliated with Whitehead Institute and Massachusetts
Institute of Technology (MIT) explain how they used a suite of novel
biological and computational methods to shed light on the question.
To start, they created two ways to systematically map the footprint
of alpha-synuclein within living cells. "In the first paper, we used
powerful and unbiased genetic tools in the simple Baker's yeast cell to
identify 332 genes that impact the toxicity of alpha-synuclein,"
explained Vikram Khurana, first and co-corresponding author on the
"Among them were multiple genes known to predispose individuals
to Parkinson's - so we show that various genetic forms of Parkinson's
are directly related to alpha-synuclein. Moreover, the results showed
that many effects of alpha-synuclein have been conserved across a
billion years of evolution from yeast to human," said Khurana, former
Visiting Scientist at the Whitehead Institute.
"In the second paper, we created a spatial map of alpha-synuclein,
cataloging all the proteins in living neurons that were in close
proximity to the protein," explained Chee Yeun Chung, former Whitehead
Institute Senior Research Scientist, who co-led both studies with
The mapping was achieved without disturbing the native
environment of the neuron, by tagging alpha-synuclein with an
enzyme - APEX - that allowed proteins less than 10 nanometers away from
synuclein to be marked with a trackable fingerprint.
"As a result, for
the first time, we were able to visualize the protein's location, at
minute scale, under physiologic conditions in an intact brain cell,"
noted Chung, who is now Scientific Co-founder and Associate Director at
Yumanity Therapeutics in Cambridge.
Remarkably, the maps derived from these two processes were closely
related and converged on the same Parkinson's genes and cellular
processes. Whether in a yeast cell or in a neuron, alpha synuclein
directly interfered with the rate of production of proteins in the cell,
and the transport of proteins between cellular compartments.
out the mechanisms of toxicity of the misfolded protein are closely
related to which proteins it directly interacts with, and that these
interactions can explain connections between different Parkinson's
genetic risk factors," said Khurana, now a Principal Investigator within
the Ann Romney Center for Neurologic Diseases at Brigham and Women's
Hospital and the Harvard Stem Cell Institute.
Finally, the authors addressed two major challenges for any study
that generates large data-sets of individual genes and proteins in model
organisms like yeast: How to assemble the data into coherent maps? And
how to integrate information across species, in this case from yeast to
Enter computational biologist Jian Peng, former Visiting Scientist
at Whitehead Institute and postdoctoral researcher at MIT. "First, we
had to figure out much better methods to find human counterparts of
yeast genes, and then we had to arrange the humanized set of genes in a
meaningful way," explained Peng, now Assistant Professor of Computer
Sciences at University of Illinois, Urbana-Champaign.
"The result was
TransposeNet, a new suite of computational tools that uses machine
learning algorithms to visualize patterns and interaction networks based
on genes that are highly conserved from yeast to humans - and then makes
predictions about the additional genes that are part of the
alpha-synuclein toxicity response in humans."
This analysis produced networks that mapped out how alpha-synuclein
is related to other Parkinson's genes through well-defined molecular
pathways. "We now have a system to look at how seemingly unrelated genes
come together to cause Parkinson's and how they are related to the
protein that misfolds in this disease," said Khurana.
To confirm their
work, the researchers generated neurons from Parkinson's patients with
different genetic forms of the disease. They showed that the molecular
maps generated from their analyses allowed them to identify
abnormalities shared among these distinct forms of Parkinson's.
this, there was no obvious molecular connection between the genes
implicated in these varieties of PD. "We believe these methods could
pave the way for developing patient-specific treatments in the future,"