ANAT3231 Cell Biology Neuronal Degeneration in Parkinsons Disease

1
ANAT3231 Cell BiologyNeuronal Degeneration in
Parkinsons Disease
Suy, Sophy
Introduction
Mitochondrial Dysfunction
alpha - Synuclein
Current and future treatments
Parkinsons Disease (PD) is a progressive
neurological disorder involving the basal
ganglia. A marked loss in the dopaminergic
neurons of the Substantia Nigra (SN) is
indicative of PD at a cellular level. Symptomatica
lly it is characterized by important diagnostic
features such as rest tremors,
bradykinesia, rigidity and postural
instability. In Australia, it is estimated that
approximately 30,000 people have PD with
the greatest prevalence in people aged 50-75.
Unfortunately the cause of PD is not clear, but
it is thought that genetic and environmental
factors (such as environmental toxins), or a
combination of them both lead to most cases of
the disease. Despite the cause not being known,
several pathological processes that may lead to
the degeneration of the neurons have been
identified. However, definitive research on which
process is actually involved has not yet been
successful. Macroscopic
Microscopic
pale SN in PD patients
normal pigmented SN
normally pigmented SN
decreased neurons and



pigments in PD patients
Drug Therapy- Drug treatments focus on restoring
dopamine levels in the Substantia Nigra or
assisting its passage within the brain. Levodopa
and dopamine agonists are examples of a current
drug therapy. Clinical trials have found some
treatments are beneficial in prolonging the life
expectancy of Parkinsons patients, with many not
showing significant clinical features of the
disease if the drug is administered prior to a
particular stage in the disease. 2 However,
drug therapy has draw backs such as toxicity to
the Substantia Nigra, physical side effects and
biochemical factors influencing the effectiveness
of the drugs in different patients. Stem Cell
Therapy- An exciting example of future treatment
of Parkinsons Disease is the use of embryonic
stem cells as a source of dopamine neurons that
can be transplanted in patients. Mesencephalic
precursor cells from the developing midbrain of
fetuses have been used as a source of
dopaminergic neurons and have been transplanted
into Parkinsons rat models. 3 These cells have
successfully developed into functional
dopaminergic neurons. However, many ethical,
medical and practical problems are limiting this
treatments potential use. For example, one
patient would require the cells from at least
five fetuses for success. As well as this
dopamine neurons have a poor survival rate of
less than 10 and tumour development is a risk
associated with stem cell therapy. Despite these
drawbacks, some successful trials have
highlighted an area with enormous potential in
future treatment options.
Schematic representation of the MD pathway
.
Oxidative Stress
Mitochondrial Dysfunction
The mechanisms of cell death in Parkinson's
disease are largely unknown. Some of the factors
that have been implicated in neuronal
degeneration in PD include mitochondrial
dysfunction (MD), oxidative stress, and
aggregation of alpha-synuclein. The
mitochondira is the 'powerhouse' of the cell
responsible for energy production. The
mitochondrial electron transport chain is
composed of a series of proteins or enzyme
complexes attached to the inner membrane of the
mitochondria i.e.cristae. In MD, complex-I
activity is impaired, resulting in energy failure
and the death of DA neurons.

• The process of MD can be summarized as follows
• involves the inhibition of complex-I by MPTP
• MPTP is a potent neurotoxin captured into acidic
  organelles, mostly lysosomes of astrocytes.
• Astrocytes contain MAO-B, which converts MPTP to
  MPP.
• The toxic product MPP, reaches the extracellular
  fluid and is transported
• into DA nerve terminals by the DA transporter.
• The accumulation of MPP within the mitochondria
  causes the inhibition of
• complex-I activity, which impairs ATP formation
  and causes disruption of
• calcium homeostasis.
• This results in the disturbances of the
  normal cell function, leading to
• cellular damage and cell death.
• MPP causes neuronal death that is marked
  by cellular shrinkage, chromatin condensation
  against the nuclear envelope, and preservation of
  organelles, as well as DNA fragmentation.

Acknowledgements
1. Guttman, G., Kish, S.J., Furukawa, Y.,
ÒCurrent Concepts in the Diagnosis and Management
of Parkinsons DiseaseÓ, Canadian Medical
Association Journal, 2003, 168, 293. 2Rajput,
A.H., ÒLevodopa prolongs life expectancy and is
non toxic to Substantia NigraÓ, Parkinsonism and
Related Disorders, 2001, 8, 95-100. 3Okano, H.,
et al., ÒIsolation and Transplantation of
Dopeminergic Neurons and Neural Stem CellsÓ.,
Parkinsonism and Related Disorders, 2002, 9,
23-28. - Sian, J., Youdin, M.B.H., Riederer, P.,
Gerlach, M., (1999), 'Neurotransmitters and
Disorders of the Basal Gamglia- MPTP induced
Parkinsonian Syndrome', Basic Neurochemistry-part
six. Inherited and Neurodegenerative Disease,
Ch.45, Lippincott Williams and Wilkins. -Savitz,S.
I., Rosenbaum, D.M., (1998), 'Apoptosis in
Neurological Disease', Neurosurgery Online,
vol.42, no.3, pp.555-574.