PTM responsible for parkinson disease

1. Parkinsons disease
Presented by: Meera Qaiser

2. What is parkinsons disease
• Parkinson's disease is the second most common
neurodegenerative disorder and the most common
movement disorder.
• The progression of Parkinson's disease and the degree of
impairment vary from individual to individual.
• In the United States, about 1 million people are affected by
Parkinson's disease and worldwide about 5 million.
• Most individuals who develop Parkinson's disease are 60
years of age or older.
• Descriptions of Parkinson's disease date back as far as 5000
BC.
• Parkinson's disease was named after the British doctor
James Parkinson, who in 1817 first described the disorder
in great detail as "shaking palsy."

3. Primary symptoms
• Tremors: Trembling in fingers, hands, arms, feet, legs, jaw,
or head.
• Rigidity: Stiffness of the limbs and trunk, which may
increase during movement.
• Bradykinesia: Slowness of voluntary movement.
• Postural instability: Impaired or lost reflexes can make it
difficult to adjust posture to maintain balance. Postural
instability may lead to falls.
• Parkinsonian gait: Individuals with more progressive
Parkinson's disease develop a distinctive shuffling walk with
a stooped position and a diminished or absent arm swing.

4. Secondary symptoms
• anxiety, insecurity, and stress
• confusion, memory loss, and dementia (more common in
elderly individuals)
• constipation
• depression
• difficulty swallowing and excessive salivation
• diminished sense of smell
• increased sweating
• male erectile dysfunction
• skin problems
• slowed, quieter speech, and monotone voice
• urinary frequency/urgency

5. S-nitrosylation of parkin
• mutations in the parkin gene are known to cause parkinson
disease.
• The parkin gene encodes an ubiquitin E3 ligase that targets
many proteins for proteasomal degradation and also has a
neuroprotective role in PD-related apoptotic events
• Mutations in the parkin gene result in the disturbances in
parkin-mediated protein ubiquitination ,which leads to the
accumulation of potentially neurotoxic protein aggregates
of parkin substrates with consequent dysfunction of the
ubiquitin-proteasome system degradative pathway.
• Interestingly, recent reports suggest that, independently
from its ubiquitin-ligase role, parkin also functions as a
transcriptional repressor of p53 to protect dopaminergic
neurons from PD-related stress.

6. continued
• In addition to these rare mutations, several
environmental toxins that trigger
oxidative/nitrosative stress are believed to
affect the enzymatic activity of parkin protein.
• Parkin has multiple cysteine residues in its
RING domain and elsewhere , which can react
with NO to form SNO-parkin.

7. continued
•
This S-nitrosylation reaction compromises parkin’s neuroprotective
function. Our group reported that S-nitrosylation of parkin initially
increases E3 ligase activity, but with additional time this activity is
inhibited. This dysfunctional E3 ligase activity is associated with
abnormal protein aggregation resembling Lewy bodies, thus
contributing to the parkinsonian phenotype
• Moreover, S-nitrosylation of parkin has also been found in brains of
human patients with Lewy body disease (LBD) and PD .
• These findings support our notion that posttranslational changes to
PD-related proteins via S-nitrosylation or other oxidation reactions
may well contribute to the PD.

8. treatment
• There is currently no treatment to cure Parkinson's disease. Several
therapies are available to delay the onset of motor symptoms.
• The most effective therapy for Parkinson's disease is levodopa
(Sinemet), which is converted to dopamine in the brain.
• However, because long-term treatment with levodopa can lead to
unpleasant side effects (a shortened response to each dose, painful
cramps, and involuntary movements), its use is often delayed until motor
impairment is more severe.
• In earlier stages of Parkinson's disease, substances that mimic the action
of dopamine (dopamine agonists), and substances that reduce the
breakdown of dopamine (monoamine oxidase type B (MAO-B) inhibitors)
can be very efficacious in relieving motor symptoms.