- Scientists have identified that
mutation in SOD1 leads to clumping of protein that destroys neurons in the
- The destruction of neurons leads
to paralysis and death in Amyotrophic Lateral Sclerosis (ALS) and other
- Phosphorylation of SOD1 prevents
clumping and death of neurons.
- Study provides new targets for
the UNC school of Medicine have shown that clumps of protein present in the
brain and the spinal cord could lead to the death of neurons by blocking their
functioning. This discovery is highly significant in neurodegenerative diseases
like Amyotrophic Lateral Sclerosis
which has no known cure.
researchers have found that the malfunctioning proteins can be reversed in a
first every study of this kind. The scientists stabilized SOD1 by demonstrating
that mutation of disease causing SOD1 could stabilize it.
‘Phosphorylation of SOD1 can prevent death of neurons in ALS.’
SOD1 and ALS
Lateral Sclerosis (ALS) is a neurodegenerative disorder that is
fatal and studies have identified that mutation in the gene
that encodes Copper-Zinc
superoxide dismutase (SOD1) could lead to a large percentage of the disease
The mutated SOD1
is found to differ from the wild type in the following ways:
Damage Caused Due to Mutant SOD1
- Higher propensity to aggregate
The native form
of SOD1 was found to react with superoxide and result
in hydrogen peroxide and oxygen radicals, lowering the effect of the
superoxide. However, mutations in SOD1 could result in the reversal of the
process, with hydrogen peroxide converted to superoxide.
Mutant SOD1 in ALS has a
greater propensity to form clumps that can lead to the damage of
neurons in the brain. The ability of mutated SOD1 to form clumps was determined
but the understanding that these clumps could lead to disease propagation was
understood from the study conducted by Ayers JI et all, the study published in
the Journal Acta Neuropathologica (2014)
. The researchers injected
spinal cord homogenates into mice and found that the aggregates spread and lead
to the disease.
Dokholyan who is a Michael Hooker Distinguished Professor of Biochemistry and
Biophysics at UNC and the senior author of the study said "The identified mutation
mimics a natural process called phosphorylation, thus suggesting that there may
be a natural, or endogenous, mechanism to stabilize SOD1 in cells and prevent
the protein from forming toxic oligomers in people without disease.
Understanding the cellular mechanisms resulting in SOD1 phosphorylation not
only offers insights about how cells respond to toxic SOD1 clumps, but will
potentially offer insights into new pharmaceutical strategies aimed at
promoting SOD1 phosphorylation. That is our immediate goal."
of Motor Neurons in ALS
that are essential for functions like breathing, talking, moving and eating are
destroyed in ALS that
leads to paralysis and death. This disease condition is also called Lou Gehrig's
Studies by Dr. Nikolay Dokholyan
Previous work on
SOD1 by Dr. Nikolay Dokholyan identified that mutated SOD 1 existed as trimers
while native versions existed as dimers.
Dr. Cheng Zhu
who is the author of the study provides an insight into the reason that leads
to the discovery to reverse SOD1 mutation "The idea was that if we can
stabilize SOD1 in the first place, we can potentially provide a way to prevent
this disease at an early stage. Our results here show that stabilizing SOD1 can
increase cell viability."
the Mutant SOD1 Clumps
structure of the SOD1 is found to be highly unstable. The researchers, in an
attempt to stabilize the, added a phosphate group, phosphorylation, that was
found to change the activity of these protein clumps.
Jimmy Fay who is
a former Lab assistant and a part of the study adds "When we transfected this
new mutation into cells in concert with the disease mutation, it actually
rescued toxicity; it made the cells not die." When asked about the significance
of the study, Fay continued "We can now see a way forward. We know that this
mutation stabilizes SOD1, and the hope is that we can find a drug that makes
the protein act in this way. By slowly piecing together the larger story of how
SOD1 acts, hopefully that can be useful in drug studies to try to get a handle
on how to affect the behavior of this protein in a planned way."
phosphorylation mimicking mutation that was introduced into the mutant SOD1
somehow prevented the killing of the neuron cells, instead of letting them
grow. This is highly significant as it opens the doorway to the following
- Potential for delaying the
progression of fatal neurodegenerative diseases like ALS.
- Only 1-2 types of ALS are caused
due to mutation in SOD1 but clumping of SOD1 is found in a lot of other
neurodegenerative diseases, which could mean that this study might be beneficial
for all those disease conditions too.
- The study shows that
phosphorylation of SOD1 could be a possible target for drug therapy.
- Other drug targets that are aimed
at preventing the clumping of SOD1 protein will benefit neurodegenerative
- SOD1 aggregation and ALS: role of metallation states and disulfide status. - (http://www.ncbi.nlm.nih.gov/pubmed/23339308)
- How do SOD1 mutations cause ALS? - (http://www.cureffi.org/2015/04/30/how-do-sod1-mutations-cause-als/)
- Experimental transmissibility of mutant SOD1 motor neuron disease - (http://www.ncbi.nlm.nih.gov/pubmed/25262000)