# Progress and Prospects in Parkinson's Research/Magazine Section/Draft article 1
## The Evolution of PD Hypotheses

   Initially PD research sought a single cause or explanation for the disease. The discovery of MPTP, which induces Parkinson symptoms virtually instantaneously, raised expectations that a single environmental toxin might be to blame. But MPTP does not occur in Nature and, although there is some epidemiological evidence of a link to certain toxins used in farming and industry, no universal candidate has come forward. Furthermore, it appeared that the disease was preceded by a long gestation period, perhaps as much as six years, when dopamine production in an individual was reducing, but positive PD symptoms had yet to appear. This is known a the Prodromal phase.
   The discovery of a PD risk in certain mutated genes raised the hope that a clear cut genetic cause might be found. However, to date, gene association testing has revealed thousands of genetic variations (SNPs). which exert a positive or negative risk influence on PD with no obvious winner. Currently the more widely held view is that a mix (or mixes) of genetic and environmental risk factors render the individual liable to the disease and determines the age of onset, but which combinations fit this picture has yet to be determined.
   But other risk factors have been recognised. An individual's risk of contracting PD can be influenced by where they live; their race and gender; traumatic events and infections; lifestyle choices and occupations The Multiple Hit Hypothesis (MHH) assumes that the reduction on the substantia nigra's capacity to generate dopamine is eroded incrementally and gradually by a series of small events or "hits", which can encompass any of the above risk factors.
   A hit can be a single event, such as a blow to the head, which takes out a cohort of dopaminergic neutrons. Alternatively it may be a recurring event such as a mutating gene, which sets up a continuously degrading situation. Or it may be an infective condition, whereby one afflicted neuron passes on the fault to its neighbours. Finally there are synergistic possibilities, where two or more risk factors interact in such a manner that their total effect is greater than the sum of their parts.
   The MHH hypothesis explains the relationship between PD risk and age, and the reason why the possession of a high risk genetic defect or exposure to a known PD-related toxin does not automatically bring on the disease. The status of this hypothesis is that it is rapidly coming into general acceptance, notwithstanding the inherent difficulties of subjecting it to scientific proof.
   A further extension to this train of thought is what might be termed the Multi Factor Hypothesis (MFH). This takes into account the observation that certain bacterial infections may affect the development of dopaminergic neurons prenataly in a gestating embryo. The evidence for this is still accumulating. This does at least provide a general explanation for early onset PD cases. This takes the point of origin back to conception. The inference of MFH is that there can be no effective prevetative cure. However improved scanning techniques migh identify the individuals most at risk, and permit some prophylactic action to be taken.

## Brain Reserves

Central to the MHH is the notion of brain reserves. Following conception, an individual develops a store of dopaminergic neurons in the substantia nigra . This increases until maturity is reached and sets an upper limit. Thereafter there is some degree of replacement and renewal, but there are also losses due to senescence, and by the end of each year the reserve shows a net deficit. Fortunately the reserve is large enough to ensure that in a normal lifespan it is not depleted to the point where a threshold is reached whereby the substantia nigra’s functionality is compromised and Parkinson’s Disease ensues.
In developed countries life expectancy is calculated as increasing by around 20 minutes each day and, given that the rate of nigral depredation stays the same, it is conceivable that if everyone lived long enough they would all contract PD. However the spare capacity is such that this is unlikely to happen in the foreseeable future.
A Person With Parkinson’s (PWP) is therefore someone whose reserve descends to the PD threshold unexpectedly earlier. Owing to some pre-natal condition they may have started with a depleted reserve, or during their life they may have experienced or come into contact with some of the numerous known PD risk factors.
A good explanation of MHH, is given by Stein et al in a comprehensive report on environmental threats to healthy aging. (This report gives an excellent account of the relationship of environmental factors with Parkinson's and is recommended reading for anyone interested in PD research.)
Fictional examples of MHH can be seen at Click on image to enlarge.

## Evidence of "hits"

The Stein paper describes a series of animals experiments with PD inducing pesticides, which showed that:-
1) Chemicals combined can act synergistically. That is, they can cause an enhanced effect that is greater than the sum of the effects of the individual chemicals.
2) Chemicals that cause toxicity through different mechanisms within the same system can have additive or synergistic effects.
3) Developmental exposures can “prime” the brain so that it is more susceptible to exposures that occur later in life. This is consistent with the concept of “multiple hits” that collectively, over time, result in clinical disease.
The paper goes on to provide citations linking PD risk with the following substances/factors:- Maneb – Paraquat – Dieldrin – Lindane – Ubiquitin-proteasome – Pyrethroids – Polyhlorinated biphenyls -- Carbon disulfide –Methanol -- n-Hexane -- Trichloroethylene – Methanol – Lead – Manganese – Copper – Iron – Zinc – Type 2 alkenes – Lipopolysaccharide (LPS) -- Formyl-methionyl-leucyl-phenylalanine - Milk – Vitamin E -- Low levels of uric acid – Obesity Head trauma – Carbon monoxide.

## The evidence of a multi-factorial origin for PD

1999
Taylor et al evaluated 140 PD cases and 147 controls for PD risk exposure. Four risk factors were statistically determined:-
* Head injury,
* Family history of PD,
* Family history of tremor,
* History of depression.
The mean interval between the first reported head injury and the onset of PD was 46.5 years, that for the first reported incidence of depression and the onset of PD was 22 years.
   PD was not associated with exposure to pesticides or herbicides. These findings support the role of both environmental and genetic factors in the etiology in PD. The results are consistent with a multifactorial model.
2003
Liu et al
   Increasing evidence suggests that early-life occurrence of inflammation in the brain, as a consequence of either brain injury or exposure to infectious agents, may play a role in the pathogenesis of PD. Most important, there may be a self-propelling cycle of inflammatory process involving brain immune cells (microglia and astrocytes) that drives the slow yet progressive neurodegenerative process. Deciphering the molecular and cellular mechanisms governing those intricate interactions would significantly advance our understanding of the etiology and pathogenesis of PD and aid the development of therapeutic strategies for the treatment of the disease.
2005
Logroscino evaluated the environmental risk factors associated with PD.
   Much evidence indicates that risk factors that have a long latency or a slow effect could be important for late-onset PD.
and:-
   Parkinson disease (PD) is of unknown but presumably multifactorial etiology. Neuropathologic studies and animal models show that exposure to environmental neurotoxicants can determine progressive damage in the substantia nigra many years before the onset of clinical parkinsonism. Therefore, PD, like other neurologic diseases related to aging, may be determined by exposures present in the environment early during the life span or even during pregnancy.
Landrigan et al reviewed the evidence for the effects of early environmental risks.
   In this article we hypothesize that environmental exposures in early life may be of particular etiologic importance and review evidence for the early environmental origins of neurodegeneration
2007
Metz examined the influence of stress upon behaviour and performance.
   Recent evidence suggests that stress modulates motor system function and influences the pathology of movement disorders...... . The dopaminergic system seems to play a central role in mediating the effects of stress on motor function. This route might also account for the finding that stress influences the pathology of dopamine-related diseases of the motor system, such as Parkinson's disease. Clinical observations have indicated that stress might lead to the onset of Parkinsonian symptoms or accelerate their progression.
2010
Perreira and Garrett assembled a cohort of 88 PD patients and 176 controls and evaluated their PD risk in relation to to life style, past history, family history, occupational history and other exposures to potential neurotoxin agents.
   The results of the study show that both familial and environmental factors may contribute to the development of PD.

## Lipopolysaccharide (LPS)

Lipopolysaccharide (LPS) is a bacteriotoxin observed in the chorioamniotic environment seen in the human population where 14% of births occur under the influence of bacterial vaginosis.
(2006)
Carvey et al exposed pregnant rats to LPS after which their offspring were delivered and allowed to develop naturally. It was found that the number of dopamine neurons in the Substantia Nigra were reduced by 25% compared to controls. Also brain inflammation was increased and there was increased susceptibility throughout life to environmental toxins.
Other observations, including the incidence of inclusions containing α-synuclein in some of the rodent brains which were reminiscent of Lewy Bodies, which suggested that these rodents were on the way to developing PD.
Telford and Hardwick put a series of e-mail questions to Prof. Carvey with the following results:-
   (1) We suggested that increasing the LPS dosage in the rodent be tried in order to see whether a PD-like condition developed which was indistinguishable from idiopathic PD. Professor Carvey replied that increasing the dose actually led to preterm delivery which, of course, compromised the experimental design. They currently are in the 17th month of determining if a PD like syndrome does naturally develop but do not know the results yet.
   (2) We suggested that the brains of offspring of LPS-treated rodents should be studied to see if other parts of the brain have deteriorated in the same way that Braak and Braak discovered in their study of human PD brains. If so, this would not only confirmthe LPS treatment as a good PD model but would then provide a reliable experimental framework for tracing the pathology of PD in detail. ProfessorCarvey said that such study is indeed underway. They are looking at the locusceruleus, the Raphe group, the basal forebrain, and the dorsal motor nucleus of the vagus to see if degeneration is also occurring in these areas.
   (3) Regarding the possibility of whether a positive correlation could be found between the incidence of PD in humans and bacterial vaginosis in the mother prenatally, Professor Carvey replied that they had talked with epidemiologists who said that it would be difficult, if not impossible, to demonstrate a positive correlation at this time since bacterial vaginosis was considered an unimportant complication of pregnancy many years ago. Putting together a prospective study would be “a tough call” until the animal data was stronger.
   (4) If scientists and clinicians agreed that indeed prenatal bacterial vaginosis might well be a genuine risk factor for PD and maybe for other neurological diseases, surely treatment regimes to eliminate it when discovered and to prevent its occurrence in the first place should be put in place as soon as possible? Professor Carvey agreed but pointed out that eliminating the bacterial contamination with antibiotics could be harmful since it would release more endotoxin. He said that the working strategy was to prevent it from occurring.
(2007)
Qin et al set out to investigate the effects of LPS.
   A single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) or tumor necrosis factor alpha (TNFalpha, 0.25 mg/kg, i.p.) injection was administered in adult wild-type mice and in mice lacking TNFalpha receptors (TNF R1/R2(-/-)).....Systemic TNFalpha and LPS administration activated microglia and LPS reduced the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra (SN) by 23% at 7-months post-treatment, which progressed to 47% at 10 months. increased expression of brain pro-inflammatory factors.....
   Together, these data demonstrate that through TNFalpha, peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated pro-inflammatory factors; (2) induce delayed and progressive loss of DA neurons in the SN. These findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson's disease.
(2008)
Miller and O’Callaghan Discussed the chronology of ADand PD>
   Suspect events in early life include infections, stress, poor nutrition, and environmental factors such as chemical and pesticide exposure. Adiposity appears to contribute to both PD and AD; and because early-life events contribute to the development of obesity, linkages may exist between early determinants of obesity and the subsequent development of these neurologic diseases..... The data for PD and AD suggest that a number of insults occurring early in life may lead or contribute to these diseases. More definitive knowledge of the key risk factors involved will be needed to implement intervention and preventative strategies early in life to dampen or prevent any adverse late-life outcomes.

## Vulnererability of the Substantia Nigra

Neurodegenerative disorders tend to strike projection neurons with long unmyelinated axons and the dopaminergic neurons of the SN are an example of these. Braak, H. et al.
Zarow et al compared neuronal loss betwen Parkinson's Disease (PD) and Alzheiner's Disease (AD):-
| Organ | AD% | PD% |
| Locus cooeruleus | 68 | 83 |
| Substantia nigra | 7 | 78 |
However in the case of PD several different pathologies may be at work here, each leading to SN neuron death.e.g.:-
* Some mutations express proteins that affect mitochondria (e.g. PINK1, DJ-1, Omi/HtrA2 and POLG).
* Some express proteins that might be involved in organelle trafﬁcking and vesicular fusion (e.g. a-syn and tau).
* Some express proteins of macromolecular degradation pathways, such as ubiquitination or ubiquitination-like degradation pathways (e.g. parkin and DJ-1) and lysosomal function(e.g. b-glucocerebrosidase).
* Some express proteins that modify oxidative stress or antioxidant function [e.g. sepiapterin, DJ-1 and ﬁbroblast growth factor-20 (FGF-20)].

## An example of LPS infection in humans

2001
Niehaus (2001) reported a case of PD in a human (herself) induced y LPS contamination.
In March 1995 a 22 year old biological laboratory assistant named Ines Niehaus was accidentally infected with LPS, which spilled out of a test tube and entered her through an open cut in her thumb. One hour later she showed the first signs of illness, which developed into neurological symptoms. Six weeks after the accident she was diagnosed with Parkinson’s Disease. As a trained scientist she was able to keep an accurate record of the progress of her illness and the effects of the treatments she tried.

## Summary

Sulzer says:-
   With PD, we seem to be dealing with a syndrome stemming from multiple etiologies that arise from a variety of interactions. Some interactions might be relatively specific for DA neurons compared with other neurons, and others might overlap with diseases such as AD and synucleinopathies in which DA neurons are relatively spared. The common features of PD, nevertheless, eventually converge at massive loss of SN DA neurons and LBs.

## Further Reading

2007
Schlect, Deborah, A.; Richfield, Eric K. and Thruchelvam, Mona. > Abstract Reproductive Toxicology 23 (3) 457 – 470 The gestational environment and Parkinson's disease: Evidence for neurodevelopmental origins of a neurodegenerative disorder.
http://www.sciencedirect.com/science/article/pii/S0890623807000263
2008
Miller, Diane B. and O'Callaghan, James P. > Abstract Metabolism 57, Suppl. 2, S44–S49 Do early-life insults contribute to the late-life development of Parkinson and Alzheimer diseases?
http://www.deepdyve.com/lp/elsevier/do-early-life-insults-contribute-to-the-late-life-development-of-rIPzte0cmI?key=elsevier
2009
Le,Weidong; Chen, Shen and Jankovic, Joseph Abstract The Neuroscientist 15 (1) 28-35 Etiopathogenesis of Parkinson Disease: A New Beginning?
http://nro.sagepub.com/content/15/1/28.short

## Related pages

PD causes