May 24, 2016
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| Illustration of Parkinson's disease by William Richard Gowers, which was first published in "A Manual of Diseases of the Nervous System" (1886). Credit: Public Domain |
After
Alzheimer's, Parkinson's disease (PD) is the leading neurodegenerative
disorder, affecting close to a million Americans, with 50,000 new cases
diagnosed every year. A progressive disorder of the nervous system affecting
movement, PD typically strikes adults in mid-life. In many cases, the spread of
the disease to other brain areas leads to Parkinson's disease dementia,
characterized by deterioration of memory, reason, attention and planning.
In
new research, Travis Dunckley, PhD., a researcher at Arizona State University's
Biodesign Institute, examines genetic modifications associated with the
development of PD and PD-associated dementia, bringing new investigative tools
to bear.
The
research, which appears in the current issue of the journal Neurology
Genetics, uses RNA sequencing to illuminate two phenomena linked with the
onset of Parkinson's disease, differential gene expression and alternative
splicing of genes.
The
study tracks specific gene alterations implicated in the development of
Parkinson's, noting that gene expression and alternative splicing offer
complementary information critical to a full understanding of disease
progression. The findings deepen the scientific understanding of the disease,
while suggesting new avenues for more comprehensive diagnosis.
"This
work shows that the degeneration of key functional brain areas in Parkinson's
disease is more genetically complex than previously appreciated," Dunckley
says. "Very small changes in the way in which genes are processed, not
just large changes in which genes are turned on or off, can contribute to
Parkinson's disease."
Dr.
Dunckley is a researcher in the newly formed Neurodegenerative Disease Research
Center, a unique partnership between Arizona State University (ASU), and Banner
Health. The research alliance focuses on advancing the scientific study,
treatment and prevention of Alzheimer's, Parkinson's and other
neurodegenerative diseases.
By
marrying Phoenix-based Banner Health, one of the nation's largest nonprofit
health systems, with the formidable resources of Arizona State University
(ASU), one of the nation's largest public research universities, the NDRC
aspires to become a national focal point for research into neurodegenerative
diseases, which affect millions of people every year and take an increasing
financial toll on an overburdened healthcare system.
The
national economic burden of PD alone amounts to tens of billions of dollars
yearly, a figure expected to grow substantially as the population ages.
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| Brain image from the Substantia nigra in Parkinson's disease, showing alpha-synuclein, a key protein implicated in the disease. Positive staining (brown) indicates an intraneural Lewy-body. Credit: Marvin 101 |
Parkinson's
disease affects roughly 1 percent of those over 50 years old, with the
incidence markedly increasing with age. Presently, there is no cure for the
disease, though medication and surgery may be used to help manage some of the
symptoms.
Neurons
located in a region of the brain known as the substantia nigra are the primary
target for Parkinson's disease. Some of these neurons produce dopamine, which
decreases as the illness advances, causing deterioration of normal movement.
Neuroinflammation,
oxidative stress, mitochondrial dysfunction and aberrant alternative splicing
have all been implicated in the trajectory of Parkinson's disease, though
precise causes of the illness—involving the deterioration of dopaminergic
neurons in the mid-brain accompanied by high rates of dementia—remain murky.
The
main symptoms of PD are tremor of the hands, arms, legs, jaw and face;
bradykinesia (or slowness of movement); stiffness and rigidity of the limbs and
trunk and impaired balance and coordination. Cell losses in other brain
regions, including the brain stem and olfactory bulb, have also been implicated
in Parkinson's.
The
primary neurological hallmark of the disease is the formation of so-called Lewy
bodies—microscopic aggregates of a protein known as α-synuclein. Lewy bodies
are involved in other neurological disorders as well, including dementia with
Lewy bodies (DLB). Evidence suggests that dementia with Lewy bodies,
Parkinson's disease and Parkinson's disease dementia may all be related to
abnormalities in brain processing of α-synuclein.
Sequence
transformation
In
the past decade, the study of gene expression has rapidly advanced, due in part
to the successful sequencing of the human genome. A suite of technologies known
as next-generation sequencing permits low-cost, rapid sequencing of DNA and
RNA, revolutionizing the study of genomics and molecular biology. Genetic
correlates of Parkinson's disease have recently been investigated, though the
mechanisms associated with cellular degeneration remain poorly understood.
In
the current study, RNA sequencing was used to evaluate differential gene
expression in a region of the brain known as the posterior
cingulate cortex, using samples from neurologically normal brains,
those with Parkinson's disease and patients with Parkinson's dementia.
Post-mortem samples from the posterior cingulate cortex were acquired from the
Banner Sun Health Research Institute Brain Bank.
Alternative
splicing occurs during gene expression and permits a single gene to code for
multiple proteins. In this process, pieces of the gene, known as exons, may be
included within or excluded from the final, processed messenger RNA (mRNA) produced from that gene. The resulting proteins translated from alternatively spliced mRNAs will contain different amino acid sequences and, often, altered biological functions. Alternative splicing allows the human genome to produce far more proteins than would be expected from its roughly 20,000 protein-coding genes. Credit: Public Domain
A
number of genes were found to be overexpressed in the two disease states when
compared with normal controls. Intriguingly, some overexpressed genes play a
role in immune function while genes responsible for cell signaling or in the
makeup of the cell's structural support network (known as the cytoskeleton)
were underexpressed in those with Parkinson's.
The
study reports on the top 20 differentially expressed genes in PD and PD
dementia, comparing these with healthy controls. Genes showing overexpression
included those involved with cell movement, receptor binding, cell signaling
and ion homeostasis. Underexpressed genes shared an involvement with hormone
signaling.
Existing
studies of gene expression in Parkinson's patients however may not tell the
whole story of genetic pathology. Alternative splicing of genes, observed in
the new research, may also be a critical factor. Applying information on
alternative splicing as well as differential gene expression provides a
more nuanced picture of how Parkinson's disease damages the brain and produces
the symptoms typically observed.
Genes
expressed and spliced
Previous
studies have implicated genetic aberrations with Parkinson's disease,
particularly mutations in a gene known as LRRK2. The new study additionally
evaluates splicing variants potentially involved with Parkinson's.
Alternative
splicing is a common mechanism of gene control, permitting a single gene to
code for multiple proteins. The process often occurs when segments of the DNA
sequence in a gene—known as exons—are skipped over during the process of
transcribing them into RNA. The alternatively spliced mRNA is then translated
into protein variants, bearing different amino acid sequences (see
illustration).
Alternative
splicing occurs in around 95 percent of human genes and is responsible for an
enormous expansion in Nature's palette of useful proteins. The phenomenon helps
to account for the staggering biological complexity and diversity in humans
despite a mere 20,000 protein-coding genes. The same process of alternative
splicing however can produce aberrant proteins linked with disease states,
including PD.
The
new study reports significant alternative splicing of disease-specific genes in
the cortex of patients with PD and PD-dementia. In particular, the researchers
examined the posterior cingulate cortex, where the spread of the PD-linked
protein α-synuclein is associated with PD dementia.
Results
showed that the genes most differentially expressed in PD are distinct from
those displaying the highest degree of alternative splicing. Hence,
conventional gene profiling alone omits important genetic information relevant
to PD development and progression. Some of the observed alternative splicing
was restricted to PD patients displaying dementia while others were associated
with PD alone.
Detailed
analysis of alternative splicing events can reveal aberrant splicing of key
disease genes. The process can drive disease progression in a number of ways.
On the one hand, alternative
splicing may provoke particular pathways to become overactive,
contributing to disease onset or progression. Alternatively, cells in distress
during the progression of PD and PD dementia may undergo altered splicing as a
result of widespread dysfunction. The authors note that future research will
help distinguish between these possibilities, shedding further light on this
devastating illness.
"It
is our hope that further clarification of the role of these newly identified
gene variants in the disease process will provide new targets for treatments
that may slow or halt the unrelenting brain degeneration."
Arizona State
http://medicalxpress.com/news/2016-05-surveys-genetic-linked-parkinson-disease.html?
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