Possible driver of Parkinson's disease
Study shows how blocking cellular housekeeping system leads to buildup
and spread of abnormal protein aggregates in the brain
Date:
February 23, 2022
Source:
Scripps Research Institute
Summary:
Study shows how blocking cellular housekeeping system leads to
buildup and spread of abnormal protein aggregates in the brain.
FULL STORY ========================================================================== Parkinson's disease may be driven in part by cell stress-related
biochemical events that disrupt a key cellular cleanup system, leading
to the spread of harmful protein aggregates in the brain, according to
a new study from scientists at Scripps Research.
==========================================================================
The discovery, published in The Journal of Neuroscience in February
2022, offers a clear and testable hypothesis about the progression of Parkinson's disease, and may lead to treatments capable of significantly slowing or even stopping it.
"We think our findings about this apparent disease-driving process are important for developing compounds that can specifically inhibit the
process of disease spread in the brain," says study senior author Stuart Lipton, MD, PhD, Step Family Endowed Chair, founding co-director of the Neurodegeneration New Medicines Center, and professor in the Department
of Molecular Medicine at Scripps Research.
Parkinson's disease affects roughly one million people in the United
States.
Its precise trigger is unknown, but it entails the deaths of neurons in
a characteristic sequence through key brain regions. The killing of one
small set of dopamine-producing neurons in the midbrain leads to the
classic Parkinsonian tremor and other movement impairments. Harm to
other brain regions results in various other disease signs including
dementia in late stages of Parkinson's. A closely related syndrome in
which dementia occurs early in the disease course is called Lewy Body
Dementia (LBD), and affects about 1.4 million people in the U.S.
In both diseases, affected neurons contain abnormal protein aggregations,
known as Lewy bodies, whose predominant ingredient is a protein
called alpha- synuclein. Prior studies have shown that alpha-synuclein aggregates can spread from neuron to neuron in Parkinson's and LBD,
apparently transmitting the disease process through the brain. But
precisely how alpha-synuclein aggregates build up and spread in this
way has been unclear.
One clue, uncovered by Lipton's lab and others in prior research,
is that the Parkinson's/LBD disease process generates highly reactive nitrogen-containing molecules including nitric oxide. In principle, these reactive nitrogen molecules could disrupt important cellular systems,
including "housekeeping" systems that normally keep protein aggregates
under control.
==========================================================================
In the new study, the Scripps Research team demonstrated the validity of
this idea by showing that a type of nitrogen-molecule reaction called
S- nitrosylation can affect an important cellular protein called p62, triggering the buildup and spread of alpha-synuclein aggregates.
The p62 protein normally assists in autophagy, a waste-management system
that helps cells get rid of potentially harmful protein aggregates. The researchers found evidence that in cell and animal models of Parkinson's,
p62 is S- nitrosylated at abnormally high levels in affected neurons. This alteration of p62 inhibits autophagy, causing a buildup of alpha-synuclein aggregates. The buildup of aggregates, in turn, leads to the secretion
of the aggregates by affected neurons, and some of these aggregates are
taken up by nearby neurons.
"The process we observed seems very similar to what is seen in Parkinson's
and LBD brains," says study first author Chang-Ki Oh, PhD, a staff
scientist in the Lipton laboratory.
The researchers also tested postmortem brains of LBD patients, and again
found that levels of S-nitrosylated p62 were abnormally high in affected
brain areas -- supporting the idea that this process occurs in humans.
Lipton and Oh say that S-nitrosylation of proteins becomes more likely
in many situations of cellular stress, including the presence of protein aggregates.
Thus, this chemical modification of p62 could be a key factor in a self- reinforcing process that not only stresses brain cells beyond their
limits, but also spreads the source of stress to other brain cells.
The team is now working to develop drug-like compounds that specifically inhibit the S-nitrosylation of p62. Although it would take years to
develop such compounds as potential commercial drugs, they could,
in principle, slow the Parkinson's/LBD disease process or prevent its
further spread in the brain after it begins, Lipton says.
The study was supported in part by the National Institutes of Health
(R01 NS086890, R35 AG071734, DP1 DA041722, R01 DA048882, RF1 AG057409,
R01 AG056259, R01 AG061845, R61 NS122098, RF1 NS123298), the Brain &
Behavior Research Foundation, and the Michael J. Fox Foundation.
special promotion Explore the latest scientific research on sleep and
dreams in this free online course from New Scientist -- Sign_up_now_>>> ========================================================================== Story Source: Materials provided by Scripps_Research_Institute. Note:
Content may be edited for style and length.
========================================================================== Journal Reference:
1. Chang-ki Oh, Nima Dolatabadi, Piotr Cieplak, Maria T. Diaz-Meco,
Jorge
Moscat, John P. Nolan, Tomohiro Nakamura, Stuart A. Lipton. S-
Nitrosylation of p62 Inhibits Autophagic Flux to Promote
a-Synuclein Secretion and Spread in Parkinson's Disease and Lewy
Body Dementia. The Journal of Neuroscience, 2022; JN-RM-1508-21 DOI:
10.1523/JNEUROSCI.1508- 21.2022 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/02/220223094316.htm
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