Transcript Bioinformatics - Indiana University

Alpha-synuclein in
Parkinson's disease
L 529 Presentation
Harini Gopalakrishnan, Keval Mehta and Sourav Roy
Outline
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Saturday, July 18, 2015
The disease
The protein
The pathway
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Parkinson’s Disease
The disease
The protein
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The pathway
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About CATPA
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Saturday, July 18, 2015
Parkinson's disease is a progressive, degenerative
neurological disorder
Symptoms are tremor, rigidity, difficulty coordinating
movement and difficulty with balance
The dopamine-producing neurons in the part of the
brain responsible for coordinating muscle movement
die or become so damaged that they are no longer
functional.
Recent findings suggest that misfolding of the protein
alpha-synuclein (aS), has been implicated in the
molecular chain of events leading to Parkinson's
disease (Ulmer et al., 2005)
There is no way to prevent its onset and once
diagnosed, it has no cure. Treatment is limited to
ameliorating symptom
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Genes Involved
The disease
The protein
The pathway
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SNCA: Synuclein, alpha (non A4 component of
amyloid precursor);
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PARK2: Parkinson disease (autosomal recessive,
juvenile) 2, parkin;
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DJ-1
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PINK1
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DRDN
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LRRK2 most recent.
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Parkinson’s disease and
α-synuclein
The disease
The protein
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The pathway
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About CATPA
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CATPA demo
Saturday, July 18, 2015
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Second most common neurodegenerative disease;
An “environmental” disease (pesticides and metals);
Due to death of dopaminergic neurons in the
substantia nigra;
Pathological hallmark is intracellular proteinaceous
inclusions called Lewy bodies and Lewy neurites;
Major protein component in LBs and LNs is αsynuclein;
Substantial evidence implicates the aggregation of αsynuclein as a key factor in the etiology of Parkinson’s
disease
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Parkinson’s diseases
The disease
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Parkinson’s disease is likely to be multifactorial
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Nine Scientific Pathways to Understanding
Parkinson ’s
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Genetic factors
Protein misfolding and aggregation
Oxidative stress
Excitotoxicity
Mitochondrial impairment
Microglial activation
Loss of trophic factors
Over-activity of basal ganglia output and
apoptosis
The protein
The pathway
About CATPA
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Saturday, July 18, 2015
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The disease
The protein
The pathway
About CATPA
CATPA demo
Saturday, July 18, 2015
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α-synuclein
The disease
The protein
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The disease is thought to be due to a toxic
overaccumulation of the protein α-synuclein; which
results in cell degeneration and death.
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One form of inherited Parkinson's is associated with
mutations in the alpha-synuclein gene that cause
overexpression of the alpha-synuclein protein
resulting in the formation of Lewy bodies.
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A more common, recessive form of inherited
Parkinson's disease is linked to a mutation in the
parkin gene. The loss of enzyme activity resulting
from this mutation leads to an accumulation of protein
substrates, including alpha-synuclein, in the cell.
The pathway
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The Pathway
The disease
The protein
The pathway
• What is known is that the O-glycosylated SNCA is
ubiquitinated and transformed into Ub SNCA, PARK2 is
believed to activate this process.
• The Ub SNCA ultimately forms the degraded Alphasynuclein through the Proteosome pathway.
• If Alpha-synuclein degradation is blocked or defective, it
aggregates to form the Lewy Body, which ultimately results
in the dopaminergic cell death
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The basal ganglia controls
movement and balance
The disease
The protein
The pathway
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Disorder in α-synuclein
The disease
The protein
The pathway
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CATPA
The disease
The protein
The pathway
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6 –Residue Repeat Region
The disease
The protein
The pathway
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Alignment Overview-1
The disease
The protein
The pathway
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Alignment Overview-2
The disease
The protein
The pathway
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CATPA DEMO
The disease
The protein
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Thanks very much!
References:
1.Ulmer et al., Structure and dynamics of micelle-bound human alphasynuclein; J.Biol.Chem. v280 pp. 9595-603, 2005.
2. Parkinson’s information website - http://www.parkinsonsinfo.com
3.Biocarta databases – http://www.biocarta.com
4.Kyoto Encyclopedia of Genes and Genomes databases –
http://www.genome.ad.jp: KEGG Kyoto Encyclopedia of Genes and
Genomes
5.National Parkinson Foundation –
http://www.parkinson.org/site/pp.asp?c=9dJFJLPwB&b=71117
6. Information hyperlinked over proteinshttp://www.ihop- net.org/UniPub/iHOP/gs/92293.html
7. Medical News Today –
http://www.medicalnewstoday.com/medicalnews.php?newsid=17028
8. American Parkinson Disease Inc - http://www.apdaparkinson.org
9. Uversky et al. Trimethylamine-N-oxide-induced folding of alpha-synuclein
FEBS Lett. 2001; 509(1):31-35.
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