Perhaps we can gain insight concerning Parkinson's disease if we begin at the end and go backward until we come to the point of insult. First, let's see if we can define an end upon which we can all agree. I will give my definition as: The neurotransmitter, dopamine, is not reaching the dopamine receptor points where it is supposed to affect fluidity of motion. This automatically leads to the question, "Why not?" This question leads to several possibilities:

1) There is no dopamine.

2) The transfer points are disabled or non-functional.

3) the receptor sites are blocked or otherwise non-functional.


Each possibility has several possible explanations, and each explanation has several possible causalities. Let's see if we can break it down from here.

michael b.

This is a possibility. If this is our assumption, then we must ask, "Why is there no dopamine?" There are several possibilities.:

a) No dopamine was transported to the transfer point.

b) No Dopamine was created.


If we assume that no dopamine was transported to the transfer point, again several ssibilities arise as to why.

1) The transport mechanism(s) are malfunctioning.

2) There was no dopamine available for transport

3) The transport of dopamine was blocked or hindered.



Am I missing anything yet?

Now the "How" questions need to be addressed as well.

Study listed in proffesional journal, dated 2004, Journal No. 127, pates 1332-1342.

Titled: "Striatal and cortical pre- and postsynaptic dopaminergic dysfunction in sporadic parkin linked parkinsonism"

Intro:Mutations in the gene designatined parkin (PARK2, OMIM 602544) recently have been identified in a number of families with autosomal-recessive juvenile parkinsonism and isolated young-onset cases.

The parkin phenotype, although in many repsects similiar to that of idiopathic Parkinson's disease (IPD) is ofter characterized by early-onset parkinsonism, foot dystonia, diurnal (having a daily cycle) fluctuations, slow progression, a good response to anticholinergics and exquisite dose sensitivity to L-Dopa, and the frequent occurrence of behavioural and neuropsychiatric complecations. Autopsied cases of parkin-linked parkinsonism have generally shown degeneration of nigral dopaminergic neurons in the abscence of Lewy body inclusions. The parkin gene on chromosome 6q25 - 27 is known to code for a u biquitin ligase involved in protein degradation presumably leading to aberrant accummulation of cell proteins resulting in neuronal dysfunction and death. (anotherwords, with parkin mutations, the missing exons which are programmed to act like antioxidents and prevent excess protein from collecting in the brain are not there. Protein chains grow freely and clog the delivery system of dopamine delivery. Dopamine continues to build up in the substanstial Niagra, until there is too much and it begins to program the L-Dopa producing neurons to die, believing it is not needed due to the high amount collecting in the Substantia Niagra that is not being used by the body).
The study used young-onset group of IPD patients negative for parkin mutations, parkin patients as well as an older group of IPD pations all matched for clinical disease severity.

Conclutions: In contrast to parkin-negative YOPD and IPD pations, parkin-linked parkinsonism is associated with more wide spread and severe disruption of striatlal dopaminergic and midbrain catecholaminergic and midbrain catecholaminergic and sertoninergic pathways. Reductions of postsynaptic D2 receptors in parkin-linked parkinsonism have been localized in striatal, thalamic and cortical. This may be a direct consequence of the genetic defect per se or a higher susceptibility to dopaminergic treatment.

Article 2 - Parkin counteracts symptoms in a Drosophila model of Parkinson's diseaase. BMC Neuroscience 2004. Electronic version found at:

http://www.biomedcentral.com/1471-2202/5/14

Conclusion: The highly conserved parkin E3 ubiquitin ligase can suppress the damaging effects of human a-synuclein. These results are consistent with a role for parkin in targeting a-synucleinto the proteasome. If this relationship is conserved in humans, this suggests that up-regulation of parkin should suppress a-wynucleinopathic PD. The development of therapies that regulate parkin activity may be cucial in the treatment of PD.

Article 3: JBC Papers in Press. Published on February 28, 2005 as Manuscript M500843200

"Parkin stabilizes microbubules through Strong Binding Mediated by Three Independent Domains"

Intro: Mutations of parkin, a protein ubiquitin E3 ligase, appear to be the most frequent cause of familial Parkinson's disease. Our previous studies have demonstrated that parkin binds strongly to a/b tubulin geterodimers and microtubules.

Article 4: Brain Journal, received November 21, 2001. Revised March 27, 2002. Accepted April 24, 2002.

Summary: Molecular and clinical characterization of parkin-associated parkinsonism is well described; however, there are no data of progression of dopamine terminal dysfunction in parkin-associated disease. We have used FDOPA PET serially to study members of a family with young-onset parkinsonism.

Conclusion: Clinically affected cases with parkin mutations showed upimg-onset paarkinsonism can have a normal life span, an dsuggests that neurodegeneration in [I]parkin[I] disease is an indolent process.

Article 5: Absolute proof of a toxin and parkin mutation cause a form of parkinsonism.

December 04, 2004

Protecting microtubule "highways" may lead to novel therapies, study shows. (microtubule highways is the system of delivery of dopamine neurons to the muscles throughout the body.) (One possible cause) Parkinson's disease may be caused by an environmental-genetic double whammy on the neurons that produce dopamine, the neurotransmitter that controls body movement, a new study as shown.

Researchers at the University of Buffalo, using cultures of rat neurons, have shown theat the presence of mutated parkin genes, combined with the toxic of the chemical rotenone, results in a cascade of highly toxic free radicals, the destruction of microtubules that transport dopaqmine to the brain
s movement center, and eventual death of the dopamine producing neuron.

This study shows how an environmental toxin and a gene linked to Parkinson's disease affect the survival of dopamine neurons by dueling on a common molecular target -- microtubules--that are critical for the survival of dopamine producing neurons," said Jian Feng, Ph.D., assistant professor of physiology and biophysics in UB School of Medicine and Biomedical Sciences and senior author.

Based on these findings, we have identified severl ways to stabilize microtubules against the onslaught of rotenone. These results ultimately may lead to novel therapies for Parkinson's disease.

Contact: Lois Bakjer
Ilbaker@buffalo.edu
716-645-5000 x1417

Any of these above articles can be obtained from the nearest University Library. I have only posted portions of articles for the sake of time.

Vicky

Hi Vicky,
Your description of the parkin phenotype and type of progression in idiopathic y/o P.D. is sooo accurate for me.
Not particularly helpful mind you! But still scarily accurate, thanks.
Regards,
Lee

To discover if you have the genetic form of PD. a company, Athenia Diagnostics, has this test commercially available. If you have the mutations, the information in the above articles will tell you the most effective drugs and the symptoms to be aware of.

My HMO paid for my test which is as simple as having some blood drawn at your doctors office and having the sample sent to Athenia Diagnostics for evaluation. It is strongly advised you speak to a Genetic Counselor for the best understanding of the test results and what affect it may have on family members if the result shows you have mutations.

Knowing that you have a mutation will affect how you choose to discuss with your neurologists the best treatment for this particular form of PD. The education process starts with patient making every test available for him/her to take to narrow down the possible treatments that will work best for him/her.

One of the available Technological tools is the DBS surgery. Because of parkin patient's oversensitivity to L-Dopa, DBS may be preferred over drugs and at a younger age, to avoid the toxic build up of synthetic Dopamine.

Vicky

http://www.athenadiagnostics.com/

PD Test
http://www.athenadiagnostics.com/sit...e.asp?test=542

Robert