[Catalyst 2019]

A New hope for parkinson’s disease:
induced neural
clearance
By luke cantu
Over 10 million people worldwide
live with Parkinson’s disease,
with few treatment options
available. 1 Parkinson’s is a
neurodegenerative disease that is the
result of the slow impairment or complete
loss of dopamine related neurons in the
area of the brain called the substantia
nigra. The substantia nigra is responsible
for motor control and inhibitory action
potentials that regulate signals throughout
the brain. The exact cause of Parkinson’s
disease is unknown; however, there
has been a connection formed between
the disease and the accumulation of a
protein called alpha-synuclein (a-syn) in
the substantia nigra neurons. A-syn is a
protein primarily found in the brain and
plays a role in maintaining a supply of
synaptic vesicles in presynaptic terminals,
meaning it is responsible for maintaining
the neurotransmitter transport that
facilitates the electrical signals between
neurons. This connection between a-syn
and Parkinson’s disease has been found
with other neurodegenerative diseases
and has prompted significant research
into the exact mechanisms responsible for
this connection. However, what precisely
causes a-syn to mutate and become
misfolded remains unknown. Finding
the cause of a-syn aggregation could be
a crucial step in curing Parkinson’s and
other neurodegenerative diseases, as
misfolded a-syn can aggregate and form
insoluble deposits, leading to complete
neuronal impairment or even death. Dr.
Laura Segatori, a professor of chemical and
biomolecular engineering at Rice University,
is pioneering research to answer these
questions. Her lab focuses on developing
methods to control protein levels, which
include engineering nanomaterials to
enhance cell clearance mechanisms, such
as the clearance of aggregated a-syn. She
has successfully reduced a-syn aggregation
by chemically inducing the Hsp70
chaperone system. Yet before this amazing
research can be discussed, a base level of
understanding about the chaperone system
must be established.
The central dogma of biology is that
information flows from DNA then to RNA
and then to protein, and this flow of genetic
information determines the function of
a protein. Often when there is a protein
misfolding,the cause is a mutation in the
genetic code that has resulted in a change
in the sequence of mRNA and subsequently,
affecting the amino acids that construct
the protein. To combat these mutations,
normal mRNA molecules use a family of
proteins called chaperones to help them
properly fold proteins. Chaperones possess
the ability to refold misfolded proteins
back into their proper form. One of the
most well documented small chaperones
is heat shock protein 70, or Hsp70 . Hsp70
posses two domains: an ATP/ADP binding
domain and a protein (substrate) binding
domain. These domains are independently
stable, bind to different substrates or
molecules, and have different properties
that determine the binding substrate and
function of the protein. When bound to
ADP, Hsp70 proteins have a high-affinity
for unfolded proteins and when bound to
ATP, have a low-affinity. Hsp70 proteins
can crowd around an unfolded substrate,
stabilize it, and prevent aggregation until
the unfolded molecule folds properly, at
which time the Hsp70s will lose affinity for
the molecule and diffuse away. An increase
in expression of Hsp70 also leads to a
decrease in cells undergoing apoptosis.
With this background in mind, Dr.
Segatori hypothesizes that “cells with an...
accumulation of aggregated proteins do
not have enough of these chaperones to
deal with these aggregated proteins.” To
investigate this phenomena, Dr. Segatori’s
Pore
Insoluble
aggregate
ATP
ATP
ATP
CIpB/Hsp104
(cross-section)
DnaK/Hsp70
chaperone system
Interaction of
CIpB/Hsp104,
DnaK/Hsp70,
& aggregate
ADP + P 1
Extraction &
threading of
polypeptide
ADP + P 1
Release of
unfolded
polypeptide
Spontaneous or
chaperonemediated
folding
22 | CATALYST