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.