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Lecture 2

BIOL 1F25 Lecture Notes - Lecture 2: Substantia Nigra, Mptp, Pars Compacta


Department
Biological Sciences
Course Code
BIOL 1F25
Professor
Gaynor E Spencer
Lecture
2

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Lecture 2
Dr. Joffre Mercier
Nov,27 2015
Side Notes:
Pesticide Exposure and Parkinson’s Disease: Epidemiological Evidence of Association
Parkinson’s disease (PD) is a movement disorder pathologically characterized by depletion of
dopaminergic (DA) cell bodies in the substantia nigra pars compacta with subsequent loss of DA
in the nigrostriatal system.
Dopaminergic: releasing or involving dopamine as a neurotransmitter. Drugs with this effect
are used in the treatment of Parkinson's disease and some psychiatric disorders; some are
subject to abuse.
Substantia Nigra: A Layer of deeply pigmented gray matter situated in the midbrain and
containing the cell bodies of a tract of dopamine producing nerve cells whose secretion
tends to be deficient in PD.
Pars compacta: Part of the SN and located in the midbrain, it is the dorsal part of
the gray matter.
Nigrostriatal System: The NS contains about 80% of the brain’s dopamine, this pathway is
involved in motor planning, dopaminergic neurons that stimulate purposeful movement.
PD is the second most common neurodegenerative disorder after Alzheimer’s disease.
It has been speculated that environmental factors might trigger a cascade of dopaminergic
nigral neuron degeneration in genetically susceptible individuals.
Various chemicals, especially pesticides, and factors related to pesticide exposure (farming, well-
water drinking, rural living) have been proposed as potential risk factors for PD.
Though many studies have been done, none have isolated a specific pesticide and PD risk.
The identification of several genes has helped researchers to determine the molecular
mechanisms involved in its pathogenesis. However, lack of a clear genetic cause have left
scientists searching for clues in the external environment.
It likely involves both genetic susceptibilities and environmental factors.
Interest in PD peaked in the 1980’s with the discovery that exposure to MPTP, similar to the
herbicide Paraquat; resulted in chronic Parkinsonism and degeneration of dopaminergic
neurons in humans.
Mechanisms involved in the underlying role of pesticides in PD include:
Oxidative stress
Interference with dopamine transporters, and mitochondrial dysfunction, inflammation.
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It has been hypothesized that in utero exposure to pesticides can inflict long-term gene
expression disturbances. Thus, possibly causing damage to substantia nigra before the onset of
PD, and the promotion of the damaged gene providing susceptibility to PD and associated
disorders.
Higher incidences of PD occur in rural, agricultural areas in comparison to urban centers. High
pesticide use areas also reported higher incidences of mortality.
Trail of Ironies to Parkinson’s Disease
The sloppy lab practices of a man synthesizing heroin-like drugs for street sale in California lead
to the identification of a chemical known as MPTP, which selectively kills cells of the Substantia
Nigra in the brain and thereby induces clinical symptoms that are identical to that of PD.
Contrary to most conclusions PD might be the consequence of long exposure to an insidious
environmental neurotoxin, which might be MPTP or something similar.
Ironically, in the late 1950’s after it was first synthesized in the lab of a major pharmaceutical
company, MPTP was tested as a potential Anti-PD drug.
Conditions found in two patient’s mimicked that of PD including:
The inability to move or speak, slow movements, tremors, expressionless face.
This was attributed to the use of an illegal heroin-like substance only after a link
between cases was found.
MPTP: Is a neurotoxin precursor to MPP+, which causes permanent symptoms of PD
by destroying dopaminergic neurons in the substantia nigra. While MPTP has no
psychoactive effects, and is not toxic itself; it can cross the blood-brain barrier and
once inside the brain is metabolised into MPP+ by an enzyme in glial cells. It leads to
cell apoptosis and build-up of free radicals, toxic molecules contributing further to
cell destruction.
An article from 1979 established the link between ingestion of MPTP and apparent PD-like
symptoms after using a meperidine-like drug synthesized in a graduate student’s personal
chemistry lab. The patient died in 1978 and had severe depletion of the cells in his substantia
nigra.
MPTP has structural similarities to certain neurotransmitters, and thus was tested as an Anti-PD
drug in the 1950’s, L-Dopa is the standard treatment and was not available at the time.
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L-Dopa: An amino acid that is the metabolic precursor of dopamine, is converted in
the brain to dopamine, and is used in synthetic form to treat Parkinson's
disease. Chemical formula: C 9 H 11 NO 4.
PD involves extensive cell death in the zona compacta region of the substantia nigra, this results
in a lack of supply of dopamine. Without a constant supply of dopamine in this region, motor
function fails and people freeze up. No one really knows why.
The development of a brain graft approach to treatment is the next step for PD: the
replacement of a dopamine supply, from adrenal tissue or even fetal tissue, for example.
Consistent therapy becomes impossible over time, the reasons are speculative: L-dopa toxicity,
excessive degeneration over time.
There is no mention of PD before 1817 (Joseph Parkinson) so it is speculated that the rise of the
industrial age brought it along. No one understands why the Substantia Nigra cells are affected
in particular.
Lecture Two Slide Notes:
Environmental Risks of Parkinson’s’ Disease(PD):
Early clues
Evidence for environmental factors
First Clues to Environmental Causes of PD(Langston et al.,1983):
Observations:
Patients:
1 female, 3 males
Ages: 26-42 years
All had history of heroin abuse(3 monthes-14 years)
Two of the patients obtained new heroin in Watsonville, in Mid-June
Two obtained heroin in San Jose, July 1st.
Symptoms are as severe as advanced PD(which develops over many years)
Generalize:
Had this been reported before?
http://www.cdc.gov/mmwr/preview/mmwrhtml/00000360.htm
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