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PARKINSON’S DISEASE: CAUSES AND PATHOGENESIS
By
Venkata Ashok Kothapalli
K00343671
INTRODUCTION
Parkinson’s disease(PD) is one of the most
common neurological disease after Alzeimer’s
disease where neurons undergoes degeneration
and this the most common disease which is seen
in the people with age of 60 years.
It was first characterized by Dr. James
Parkinson in the book named “An Essay on the
Shaking Palsy”, reported in 1817. It was known
as shaking palsy and it is idiopathic which is
unknown of its cause.
In this disorder mainly a group of neuronsthat produce dopamine are degenerated which inresult affects the motor system. It is a chronic andprogressive disorder of nervous system whicheffects movements that mean the symptoms maycontinue and worsen by time to time.
It majorly involves in malfunction of neurons,which primarily affects substantial nigra of thebrain. It indirectly decreases the dopamine contentof brain by reducing the neurons level which makesunable to control movement.
SYMPTOMS:
• Tremors are observed mainly in parts like limbs,
legs, jaws, face.
• Bradykinesia.
• Rigidity in limbs and trunks are observed.
• Postural instability.
• Impairment in balance and coordination.
STAGES IN PARKINSON’S
DISEASE
STAGE 1 STAGE 2 STAGE 3 STAGE 4 STAGE 5
Mild
unsevere
symptoms
Moderate
symptoms
with facial
modifications
Progression
of disease is
occurred.
Drastic
change is
observed.
Advanced
stage with
aggressive
symptoms
Tremors on
one side and
postural
changes are
observed.
Tremors on
both sides of
the body is
observed.
Imbalance of
body and
improper
reflexes are
observed.
Personal
assistance is
required
even in
simple tasks.
Hallucination
and spasm
occurs in this
stage.
DIAGRAMMATIC REPRESENTATION OF
NIGROSTRIATAL PATHWAY
In PD, degeneration of nigro-straiatalpathway is observed which results in loss ofdopaminergic neurons the drastic loss ofneurons resembles the putamen structuresand modest loss of neurons resemblescaudate structures.
The diagram illustrates discoloration (loss ofdark brown pigment called neuro-melanin,represented in arrows) of the SNpc due toloss of dopaminergic neurons.
IMMUNOCHEMICAL LABELLING
OF INTRANEURONAL INCLUSIONS
When immunostainig was performed
with antibodies of synuclein, where
antibodies are rounded partially by
immunoreactive substance.
Due to this staining the more dense
lewis bodies are observed in the right side of
picture which reveals the occurrence of
parkinson’s disease.
PATHOGENESIS
The core pathology of PD affects the dopamine-producing neurons of thesubstantial nigra (SN).
Dopamine is an important neurotransmitter.
The functions of dopaminergic pathways divide broadly into:
• Motor control (nigrostriatal system)
• Behavioral effects (mesolimbic and mesocortical systems)
• Endocrine control (tuberohypophyseal system).
But in PD nigrostriatal system is damaged, effecting the motor control.
SN neurons synthesized dopamine from
DOPA which is carried by neurons to the striatum.
Around 75% of the dopamine is presented in the
substantial nigra of the nigrostriatal pathway in the
brain.
Zonal compacta is the mid part of substantial
nigra which plays a major role in early and
advanced stages of parkinson’s disease.
Patients with parkinson’s disease diagnosed,
dopamine content is found to be low in striatal parts
of brains and is less compared with other
neurotransmitters such as noradrenaline and 5-
hydroxy tryptamine.
FACTORS
• Genetical factors: Protein aggrretion like proteinmiss-folding, in which α-synuclein plays animportant role in PD.
• Oxidative stress: In this free radicals aregenerated in brain, degenerates the dopaminergicneurons that results in parkinson’s disease.
• Extrapyramidal motor system defects.
• Environmental factors.
• Age related risk factor.
PROTEIN AGGREGATION
α-Synuclein:
Lewis bodies which are observed in PDaffected person are formed due to α-synuclein protein aggregation in the brainwhich leads to the degeneration of thedopaminergic neurons.
This aggregation of protein occurs due to themisfolding of the precursor molecules of α-synuclein during its formation.
In this misfolding generally the hydrophobic
residues that would normally be buried in the core
and the protein are exposed on its surface, which
gives the molecules a strong tendency to aggregate,
initially as oligomers, and then as insoluble
microscopic aggregates.
Accumulation of insoluble proteins in the neurons
leads to formation of lewis bodies.
At earlier stage the lewis bodies are first seen in
olfactory bulb, medulla oblongata and pontine
tegmentum.
As the progression of disease occurs lewis
bodies start developing in the major parts of
substantial nigra such as midbrain and forebrain and
finally found in neuronal cortex as these parts of the
brain majorly responsible for the Parkinson's
disease.
This lewis bodies stick to neuron cell
membranes. Results in the degeneration of the
neuron because of impermeability of the cell
membrane.
OXIDATIVEE STRESS:
This is one of the major degrdative
pathway in which peroxide radical was
produced by either deamination of dopamine
by monoamine oxidases A and B or by
fenton-type reactions with ferrous or cupric
ions.
Peroxide radical is also formed by
reacting dopamine with oxygen to form
quinones and semiquinones forming
hydrogen peroxide and superoxide.
EXTRAPYRAMIDAL MOTOR
SYSTEM DEFECTS:
Cholinergic interneurons of the corpus
striatum are also involved in PD disease.
Acetylcholine release from the striatum is
strongly inhibited by dopamine, and it is
suggested that hyperactivity of these
cholinergic neurons contributes to neuro-
degeneration causing the symptoms of PD.
Simplified diagram of the organization of the
extrapyramidal motor system and the defects
that occur in Parkinson's disease (PD) a.
Normally, activity in nigrostriatal dopamine
neurons causes excitation of striatonigral
neurons and inhibition of striatal neurons that
project to the globus palidus.
In PD, the dopaminergic pathway from the
substantial nigra to the striatum is impaired.
ENVIRONMENTAL FACTORS
• Exposure to different pesticides, injury to the
head are the major factors.
• Drinking of local water in the rural areas may
cause exposure directly to the chemicals in water.
• Agents like insecticides mainly chloropyrifos &
organo chlorines and rotenone or paraquat as
pesticides may affect the body cause the
accumulation in body leads to PD.
• Exposure of heavy metals to the body may cause
accummalation of metals in substantial nigra.
AGING A RISK FACTOR:
Striatal dopamines may loose from the
dopaminergic neurons by the age and time
this leads to parkinson’s disease.
In aged persons reactive microglia's are
less in substantia nigra in brain which leads
to active destruction of neurons.
CONCLUSION
Here to conclude that genetic factors
are majorly involved in parkinson’s disorder
in which dopaminergic neurons are
degenerated and even environmental factors,
age risk factor also plays an important role in
degeneration of neurons i.e., parkinson’s
disease.
REFERENCES
William Dauer1,3 and Serge Przedborski,
Neuron, Vol. 39, 889–909, September 11, 2003.
Frank J.S. Lee, Fang Liu Volume 58, Issue 2,
August 2008, Pages 354–364.
H. P. Rang, M. M, Dale, J. M. Ritter, 6th edition
rang and dales pharmacology.
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