[Catalyst 2019]

Normal
Parkinson’s Diseas e
Movement
Disorders
Cell Death
Dopaminer gic Neuron
Substantia
Nigra
A-syn Monomers
A-syn
Oligomers
A-syn
Aggregate
approach involves nanoparticles with
a surface layer that contains different
chemical and physical properties that
allows them to interact with different parts
of the cell in specific ways. For example,
nanoparticles in drug delivery that are
engineered for membrane passage allow
for the drug to be transported to the place
of action that the drug would not reach
on its own. Thus, the drug’s influence on
targeted tissues can be optimized and the
undesirable side effects on vital organs can
be minimized along with protecting the
drug from rapid degradation or clearance. 2
This same concept is applied with Dr.
Segatori’s work; she designs nanoparticles
that have specific chemical properties such
as polarity or solubility that allow for them
to pass cellular membranes and specifically
bind to different parts of DNA. This in turn
induces changes with the chaperone system
without inadvertently affecting other parts
of the cell. Another unique approach by
Dr. Segatori is the use of colocalization,
which employs fluorescence microscopy.
Fluorescence microscopy is when specific
proteins or molecules in a cell are stained
or made to have a specific fluorescence
through genetic alteration and are then
viewed through a fluorescent microscope.
Colocalization is simply observing if the
different fluorescent “targets” are located in
the same area of the cell or very near to one
another. This allows for the quantification
of aggregated proteins in a cell before and
after an induction of Hsp70 to determine if
there is a relationship between Hsp70 and
aggregated protein levels.
The purpose of Dr. Segatori’s research is
to demonstrate a proof of principle study
that would then allow for the further
investigation of utilizing nanoparticles to
upregulate Hsp70. In one study, Dr. Segatori
investigated the effects of carbenoxolone, a
chemical compound previously reported to
upregulate Hsp70, in human neuroglioma
cells (a model for substantia nigra neurons)
overexpressing a-syn. 3 By introducing
carbenoxolone into a cell and analyzing the
proteins present with colocalization, it was
found that carbenoxolone increased the
presence of Hsp70 by 52% and decreased
the probability of protein aggregation
from 67% to 37.2%.3 By establishing a
relationship between Hsp70 levels and
protein aggregation, researchers can
develop ways to induce changes in cell
systems to clear aggregated proteins. With
these findings, Dr. Segatori is currently
working on a new way of tackling the
problem of protein aggregation by
designing a nanoparticle that could cause
a system level change or, “essentially
reprogram the cell to respond to a stimulus
associated with a phenotypic trait of a
disease.” Dr. Segatori is searching for a
way to design a genetic circuit to interface
with these pathways and modulate the
response of cell in response to a stimulus.
Such stimulus could be the aggregation of
protein which, through the genetic circuit,
could then be linked to the ability of the cell
to induce the chaperone system to respond
to the stimulus. Then once the stress is
removed the chaperone system would
subside, hence resulting in a feedback loop.
However, there are still challenges, such
as ensuring nanoparticle passage across
the highly selective blood brain barrier and
designing a nanoparticle with a specific
genetic alterations to enact system wide
change.
The application of Dr. Segatori’s work is
limitless, but she is currently investigating
how the use of her nanoparticles could
activate clearance activity within neurons in
an attempt to prevent neurodegenerative
diseases. Dr. Segatori relates her research
and its possible applications to a two
sided coin: “This is a side of the same
coin, on one hand you are thinking of
developing a treatment for a disease, a
treatment for aggregated proteins that is
not just Parkinson’s but also misfolding
protein diseases. On the other side there is
understanding how to design nanoparticles
that will interface with biological systems.”
This dichotomy is the future of her work
and all work in biological nanoparticles.
Works Cited
[1] P. (2019, March 28). Statistics. Retrieved
from https://www.parkinson.org/
Understanding-Parkinsons/Statistics
[2] Uddin, M. D. (2019). Nanoparticles
as Nanopharmaceuticals: Smart Drug
Delivery Systems. Nanoparticulate
Drug Delivery Systems, 85-120.
doi:10.1201/9781351137263-3
[3] Kiri Kilpatrick, Jose Andres Novoa,
Tommy Hancock, Christopher J. Guerriero,
Peter Wipf, Jeffrey L. Brodsky, and Laura
Segatori ACS Chemical Biology 2013 8 (7),
1460-1468
[4] Ruipérez, V., Darios, F., & Davletov,
B. (2010). Alpha-synuclein, lipids and
Parkinson’s disease. Progress in Lipid
Research, 49(4), 420-428. doi:10.1016/j.
plipres.2010.05.004
DESIGN BY Luke Cantu
EDITED BY Minjung Kim
CATALYST | 23