How different diseases originate with slightest changes in proteins. Understanding ALS , Parkinson, Alzhiemer , Taupathies development which may lead to their treatment!

2. CONTENTS
 Introduction
 Overview of folding
 Fatality via proteins
 Major PMD
 Pathological manifestation of PMD
 Conclusion

3. INTRODUCTION
 Protein folding is a complex process involving complex
role of kinetic and thermodynamic barriers.
 Slight perturbation or single amino acid change leads to
misfolded forms of protein.
 The aggregation process is a key event leading to
damage.
 The misfolded forms tend to disrupt the biological
processes leading to fatal diseases.

4. OVERVEIW OF FOLDING
 Folding in natural way
 Folding stages and energy landscape
 Misfolding of proteins

5. In vivo protein folding
pathway

6. Energy landscape of protein
folding

7. Misfolding

8. Fatality via proteins
Misfolding Aggregation
Disruption of
cellular/
extracellular
processes
• Misfolded
forms
• Supersaturation
mediated
aggregation
• Complex
orphan proteins

9. Major misfolded forms
Oligomeric
species
Fibrillar
structures
Off-pathway
aggregates
Amorphous
aggregates

10. What makes oligomers toxic
OLIGOMERS vs FIBRILS
 In oligomers hydrophobic surfaces are exposed in β-
sheets while hidden in stacks in fibrils
 Oligomers are smaller in size so can easily diffuse in
tissues as compared to longer fibrils
 The more number of open active ends present in case
of oligomers than fibrils allow improved interaction of
oligomers with cellular targets.
 Oligomers are highly unstable disordered structures
whereas fibrils are stable organized molecules.

11. SUPERSATURATION IS A MAJOR DRIVING FORCE FOR
PROTEIN AGGREGATION
The supersaturation score δu, which measures the tendency of proteins
to aggregate from the unfolded state, is based on the Zyggregator score
(Zagg) and mRNA expression levels.The supersaturation
score δf , which measures the tendency of proteins to aggregate from the
folded state, is based on the structurally corrected Zyggregator score
Cell Reports 5, 781–790, November 14, 2013

13. Model of supersaturation leading to aggregation
Supersaturated proteins in
Alzheimer’s disease. (A)
Organization of the proteins
involved in the primary (proximal)
and secondary (distal) events in
the amyloid cascade hypothesis .
According to this hypothesis the
initial aggregation of Ab triggers a
series of proximal events (inner
ring, blue scale), which is then
followed by another series of
distal events involving proteins in
the same networks (outer ring,
gray scale). Supersaturation
scores are scaled from green (low
scores) to red (high scores).
 Correlated expression and control by sameTFs
Trends in Pharmacological Sciences, February 2015, Vol. 36, No. 2

14. Complex-orphan proteins
Biophys J. 2011 Apr 20; 100(8): 2033–2042.
Ataxin-3 protein associated with
spinocereberalataxia (SCA)
‘Complex orphan proteins’,
that is proteins that would
normally be present in the
cell as part of large
molecular assemblies that
protect them from
aggregation.When either
produced in isolation or
factors intervene to
prevent this status, they
will develop an elevated
tendency to self-associate
or unfold..

15. MAJOR PMD
AD(Amyloids)
Parkinson
(α synuclein )
Tau
(Frontotemporal
dementia / AD)
Prions
(MSA/CJD)
Huntington

16. Alzheimer's Disease
• Linkage studies
identified 3
genes for
multiple
mutation ( APP,
PSEN1,
PSEN2).
• IncreasedAβ40
andAβ42 ,
aggregation
and increased β
and γ secretase

17. Parkinson
A53T ,A30P and
E46K mutation
is responsible
for generation
of misfolded
form
Natively unfolded
converts to β
sheets

18. Taupathies
 Hyperphosphorlation
of microtubule
associated protein.
 Stress-activated
kinase, c-Jun
N terminal kinase
(SAPK/JNK) and kinase
p38 in brain
homogenates are
involved in all the
Hyperphosphorylation
associated
taupathies.

19. Prions
 Normal cell membrane protein, if mutated forms into transmissible
infectious protein
NEUROTOXIC PEPTIDE
 The highly amyloigenic and hydrophobic palindromeAGAAAAGA is
located between aa residue 113 and 120 of PrP 106-126 is responsible
for conversion of α helices to β sheets.
Curr Mol Med. 2009 Sep; 9(7): 826–835.

20.  The disease-causing
agents are
PrPSc aggregates that
act as templates for
the conversion; its
catalytic activity
depends on the size of
the particle.
PrPScparticles which
consist of only 14-28
PrP molecules exhibit
the highest rate of
infectivity and
conversion

21. Huntington
 Poly Q repeats leading to
misfolding and aggregation

22. Other Fatal PMDs
 The alanine-to-valine
substitution at position 4
of SOD1 (SOD1A4V)
 Hydrogen peroxide or
nitronium ion can react
with reduced SOD1
(SOD1-Cu+). Molecular
oxygen (O2) can react
aberrantly with Zn-
deficient SOD1 to
generate an excess of
superoxide anion .The
unstable protein could
also release free copper
and/or zinc, which might
be toxic.
J Mol Biol. 2012 Aug 24;421(4-5):631-52
Amylo Lateral Sclerosis

23. • Systemic Amyloidosis
• V30M point mutation disruption of tetramer
to monomer
Transerythin
• Dialysis-related amyloidosis (DRA)
• Truncated form lacking the 6 N-terminal
residues (DN6) .
β2-
Microglobulin
• Type 2 diabetes and the loss of islet β cells
• Conversion of the helix region into β sheet
structure or by impaired processing of pro
IAPP N-terminus
Amylin/ islet
Amyloid
polypeptide
(IAPP)

24. Pathological manifestation of PMD
 Calcium homeostasis mediated apoptosis
 Plasma membrane interaction disrupting cell-cell
communication
 Cell organelle’s toxicity
 Neuronal degradation
 Atherosclerosis

26. Conclusion
 The way proteins fold determine the level of
toxicity they will induce.
 Supersaturation state leading to aggregation
determines the level of fatality
 Diseases belonging to PMD category are
much inclined to β structures as they are
most stable forms.

27. THANKYOU!