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