I'm wokring on the synaptic junction right now and I wanted to know its exact working... I learnt about it but I want to know what happens exactly when Parkinson's disease gets in... If you explain these two things to me, I'll be very grateful to you.

I wish this will help you as it mentions clearly.

Remy P, Samson Y.
The role of dopamine in cognition: evidence from functional imaging studies.Curr Opin Neurol. 2003 Dec;16 Suppl 2:S37-
41. Review.

http://courses.washington.edu/chat543/cvans/sfp/catechol.html

Also

http://mr.caltech.edu/media/Press_Releases/PR13192.html

http://www.neuron.org/content/article/abstract?uid=PIIS0896627308008106

http://www.neuron.org/content/article/abstract?uid=PIIS0896627308007563
Or
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSS-4TMK33J-G&_user=1010281&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_version=1&_urlVersion=0&_userid=1010281&md5=5a67f9ad81da0af141acf456b91d2fb8

I could recommend a whole host of journal articles and reviews that would help answer your question, but I don't know which you will be able to access due to your institution's online subscriptions.

The best search to perform is to go to

http://www.ncbi.nlm.nih.gov/sites/entrez

and search the "Pubmed" database with the search term


Parkinson's disease AND "review"[Filter]

This will bring up 9043 reviews through which you can look for relevant articles.

If you want to narrow your search to more recent years you can add the the year you want to search like this

2007[pdat]

so the search will actually read

Parkinson's disease AND "review"[Filter] AND 2007[pdat]

You can change the year to whatever one you want. many journals begin to make articles free to view online after they are over 12 months old or you may find something useful in one of the open access journals like PLoS Biology or BMC Neuroscience.

Good luck

here are some references to open access articles on Parkinson's Disease from PloS Biology

if you want to perform the search yourself so that you can click straight through to the articles go to

http://www.ncbi.nlm.nih.gov/sites/entrez

and search for

"PLoS Biology"[Jour] AND Parkinson's disease


1: PLoS Biol. 2008 Jul 29;6(7):e170.

Protein aggregation and protein instability govern familial amyotrophic lateral
sclerosis patient survival.

Wang Q, Johnson JL, Agar NY, Agar JN.

Department of Chemistry, Brandeis University, Waltham, Massachusetts, USA.

The nature of the "toxic gain of function" that results from amyotrophic lateral
sclerosis (ALS)-, Parkinson-, and Alzheimer-related mutations is a matter of
debate. As a result no adequate model of any neurodegenerative disease etiology
exists. We demonstrate that two synergistic properties, namely, increased protein
aggregation propensity (increased likelihood that an unfolded protein will
aggregate) and decreased protein stability (increased likelihood that a protein
will unfold), are central to ALS etiology. Taken together these properties
account for 69% of the variability in mutant Cu/Zn-superoxide-dismutase-linked
familial ALS patient survival times. Aggregation is a concentration-dependent
process, and spinal cord motor neurons have higher concentrations of
Cu/Zn-superoxide dismutase than the surrounding cells. Protein aggregation
therefore is expected to contribute to the selective vulnerability of motor
neurons in familial ALS.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

PMID: 18666828 [PubMed - in process]

2: PLoS Biol. 2008 Jan;6(1):e6.

Conformational equilibria in monomeric alpha-synuclein at the single-molecule
level.

Sandal M, Valle F, Tessari I, Mammi S, Bergantino E, Musiani F, Brucale M,
Bubacco L, Samorì B.

Department of Biochemistry G. Moruzzi, University of Bologna, Bologna, Italy.

Human alpha-Synuclein (alphaSyn) is a natively unfolded protein whose aggregation
into amyloid fibrils is involved in the pathology of Parkinson disease. A full
comprehension of the structure and dynamics of early intermediates leading to the
aggregated states is an unsolved problem of essential importance to researchers
attempting to decipher the molecular mechanisms of alphaSyn aggregation and
formation of fibrils. Traditional bulk techniques used so far to solve this
problem point to a direct correlation between alphaSyn's unique conformational
properties and its propensity to aggregate, but these techniques can only provide
ensemble-averaged information for monomers and oligomers alike. They therefore
cannot characterize the full complexity of the conformational equilibria that
trigger the aggregation process. We applied atomic force microscopy-based
single-molecule mechanical unfolding methodology to study the conformational
equilibrium of human wild-type and mutant alphaSyn. The conformational
heterogeneity of monomeric alphaSyn was characterized at the single-molecule
level. Three main classes of conformations, including disordered and "beta-like"
structures, were directly observed and quantified without any interference from
oligomeric soluble forms. The relative abundance of the "beta-like" structures
significantly increased in different conditions promoting the aggregation of
alphaSyn: the presence of Cu2+, the pathogenic A30P mutation, and high ionic
strength. This methodology can explore the full conformational space of a protein
at the single-molecule level, detecting even poorly populated conformers and
measuring their distribution in a variety of biologically important conditions.
To the best of our knowledge, we present for the first time evidence of a
conformational equilibrium that controls the population of a specific class of
monomeric alphaSyn conformers, positively correlated with conditions known to
promote the formation of aggregates. A new tool is thus made available to test
directly the influence of mutations and pharmacological strategies on the
conformational equilibrium of monomeric alphaSyn.

Publication Types:
Research Support, Non-U.S. Gov't

PMID: 18198943 [PubMed - indexed for MEDLINE]

3: PLoS Biol. 2007 Dec;5(12):e334.

Out FOXing Parkinson disease: where development meets neurodegeneration.

Wexler EM, Geschwind DH.

Division of Geriatric Psychiatry and the Program in Neurobehavioral Genetics,
University of California at Los Angeles, Los Angeles, California, United States
of America. ewexler@ucla.edu

PMID: 18092892 [PubMed - indexed for MEDLINE]

4: PLoS Biol. 2007 Dec;5(12):e325.

The foxa2 gene controls the birth and spontaneous degeneration of dopamine
neurons in old age.

Kittappa R, Chang WW, Awatramani RB, McKay RD.

Laboratory of Molecular Biology, National Institute of Neurological Disorders and
Stroke, National Institutes of Health, Bethesda, Maryland, United States of
America.

Parkinson disease affects more than 1% of the population over 60 y old. The
dominant models for Parkinson disease are based on the use of chemical toxins to
kill dopamine neurons, but do not address the risk factors that normally increase
with age. Forkhead transcription factors are critical regulators of survival and
longevity. The forkhead transcription factor, foxa2, is specifically expressed in
adult dopamine neurons and their precursors in the medial floor plate. Gain- and
loss-of-function experiments show this gene, foxa2, is required to generate
dopamine neurons during fetal development and from embryonic stem cells. Mice
carrying only one copy of the foxa2 gene show abnormalities in motor behavior in
old age and an associated progressive loss of dopamine neurons. Manipulating
forkhead function may regulate both the birth of dopamine neurons and their
spontaneous death, two major goals of regenerative medicine.

Publication Types:
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

PMID: 18076286 [PubMed - indexed for MEDLINE]

5: PLoS Biol. 2007 Jul 17;5(7):e206. [Epub ahead of print]

Mitochondrial Cell Death Control in Familial Parkinson Disease.

Kroemer G, Blomgren K.

PMID: 17638420 [PubMed - as supplied by publisher]

6: PLoS Biol. 2007 Jun 19;5(7):e172. [Epub ahead of print]

PINK1 Protects against Oxidative Stress by Phosphorylating Mitochondrial
Chaperone TRAP1.

Pridgeon JW, Olzmann JA, Chin LS, Li L.

Mutations in the PTEN induced putative kinase 1 (PINK1) gene cause an autosomal
recessive form of Parkinson disease (PD). So far, no substrates of PINK1 have
been reported, and the mechanism by which PINK1 mutations lead to
neurodegeneration is unknown. Here we report the identification of TNF
receptor-associated protein 1 (TRAP1), a mitochondrial molecular chaperone also
known as heat shock protein 75 (Hsp75), as a cellular substrate for PINK1 kinase.
PINK1 binds and colocalizes with TRAP1 in the mitochondria and phosphorylates
TRAP1 both in vitro and in vivo. We show that PINK1 protects against
oxidative-stress-induced cell death by suppressing cytochrome c release from
mitochondria, and this protective action of PINK1 depends on its kinase activity
to phosphorylate TRAP1. Moreover, we find that the ability of PINK1 to promote
TRAP1 phosphorylation and cell survival is impaired by PD-linked PINK1 G309D,
L347P, and W437X mutations. Our findings suggest a novel pathway by which PINK1
phosphorylates downstream effector TRAP1 to prevent oxidative-stress-induced
apoptosis and implicate the dysregulation of this mitochondrial pathway in PD
pathogenesis.

PMID: 17579517 [PubMed - as supplied by publisher]

7: PLoS Biol. 2007 Mar;5(3):e39.

Absence of Ret signaling in mice causes progressive and late degeneration of the
nigrostriatal system.

Kramer ER, Aron L, Ramakers GM, Seitz S, Zhuang X, Beyer K, Smidt MP, Klein R.

Department of Molecular Neurobiology, Max-Planck Institute of Neurobiology,
Martinsried, Germany. ekramer@neuro.mpg.de

Support of ageing neurons by endogenous neurotrophic factors such as glial cell
line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor
(BDNF) may determine whether the neurons resist or succumb to neurodegeneration.
GDNF has been tested in clinical trials for the treatment of Parkinson disease
(PD), a common neurodegenerative disorder characterized by the loss of midbrain
dopaminergic (DA) neurons. BDNF modulates nigrostriatal functions and rescues DA
neurons in PD animal models. The physiological roles of GDNF and BDNF signaling
in the adult nigrostriatal DA system are unknown. We generated mice with
regionally selective ablations of the genes encoding the receptors for GDNF (Ret)
and BDNF (TrkB). We find that Ret, but not TrkB, ablation causes progressive and
adult-onset loss of DA neurons specifically in the substantia nigra pars
compacta, degeneration of DA nerve terminals in striatum, and pronounced glial
activation. These findings establish Ret as a critical regulator of long-term
maintenance of the nigrostriatal DA system and suggest conditional Ret mutants as
useful tools for gaining insights into the molecular mechanisms involved in the
development of PD.

Publication Types:
Research Support, Non-U.S. Gov't

PMID: 17298183 [PubMed - indexed for MEDLINE]

8: PLoS Biol. 2006 Jan;4(1):e6.

Functional amyloid formation within mammalian tissue.

Fowler DM, Koulov AV, Alory-Jost C, Marks MS, Balch WE, Kelly JW.

Department of Chemistry, The Skaggs Institute of Chemical Biology, The Scripps
Research Institute, La Jolla, California, USA.

Amyloid is a generally insoluble, fibrous cross-beta sheet protein aggregate. The
process of amyloidogenesis is associated with a variety of neurodegenerative
diseases including Alzheimer, Parkinson, and Huntington disease. We report the
discovery of an unprecedented functional mammalian amyloid structure generated by
the protein Pmel17. This discovery demonstrates that amyloid is a fundamental
nonpathological protein fold utilized by organisms from bacteria to humans. We
have found that Pmel17 amyloid templates and accelerates the covalent
polymerization of reactive small molecules into melanin-a critically important
biopolymer that protects against a broad range of cytotoxic insults including UV
and oxidative damage. Pmel17 amyloid also appears to play a role in mitigating
the toxicity associated with melanin formation by sequestering and minimizing
diffusion of highly reactive, toxic melanin precursors out of the melanosome.
Intracellular Pmel17 amyloidogenesis is carefully orchestrated by the secretory
pathway, utilizing membrane sequestration and proteolytic steps to protect the
cell from amyloid and amyloidogenic intermediates that can be toxic. While
functional and pathological amyloid share similar structural features, critical
differences in packaging and kinetics of assembly enable the usage of Pmel17
amyloid for normal function. The discovery of native Pmel17 amyloid in mammals
provides key insight into the molecular basis of both melanin formation and
amyloid pathology, and demonstrates that native amyloid (amyloidin) may be an
ancient, evolutionarily conserved protein quaternary structure underpinning
diverse pathways contributing to normal cell and tissue physiology.

Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

PMID: 16300414 [PubMed - indexed for MEDLINE]

9: PLoS Biol. 2005 Aug;3(8):e271. Epub 2005 Aug 2.

Dopamine-independent locomotor actions of amphetamines in a novel acute mouse
model of Parkinson disease.

Sotnikova TD, Beaulieu JM, Barak LS, Wetsel WC, Caron MG, Gainetdinov RR.

Department of Cell Biology, Center for Models of Human Disease, Institute for
Genome Sciences and Policy, Duke University Medical Center, Durham, North
Carolina, USA.

Brain dopamine is critically involved in movement control, and its deficiency is
the primary cause of motor symptoms in Parkinson disease. Here we report
development of an animal model of acute severe dopamine deficiency by using mice
lacking the dopamine transporter. In the absence of transporter-mediated
recycling mechanisms, dopamine levels become entirely dependent on de novo
synthesis. Acute pharmacological inhibition of dopamine synthesis in these mice
induces transient elimination of striatal dopamine accompanied by the development
of a striking behavioral phenotype manifested as severe akinesia, rigidity,
tremor, and ptosis. This phenotype can be reversed by administration of the
dopamine precursor, L-DOPA, or by nonselective dopamine agonists. Surprisingly,
several amphetamine derivatives were also effective in reversing these behavioral
abnormalities in a dopamine-independent manner. Identification of dopamine
transporter- and dopamine-independent locomotor actions of amphetamines suggests
a novel paradigm in the search for prospective anti-Parkinsonian drugs.

Publication Types:
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

PMID: 16050778 [PubMed - indexed for MEDLINE]

10: PLoS Biol. 2004 Nov;2(11):e401. Epub 2004 Nov 16.

Molecules that cause or prevent Parkinson's disease.

Cookson MR.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of
Health, Bethesda, Maryland, USA. Cookson@mail.nih.gov

Publication Types:
Review

PMID: 15547643 [PubMed - indexed for MEDLINE]

11: PLoS Biol. 2004 Nov;2(11):e362. Epub 2004 Oct 5.

DJ-1 is a redox-dependent molecular chaperone that inhibits alpha-synuclein
aggregate formation.

Shendelman S, Jonason A, Martinat C, Leete T, Abeliovich A.

Department of Pathology, Center for Neurobiology and Behavior, and Taub
Institute, Columbia University, College of Physicians and Surgeons, New York, New
York, USA.

Parkinson's disease (PD) pathology is characterized by the degeneration of
midbrain dopamine neurons (DNs) ultimately leading to a progressive movement
disorder in patients. The etiology of DN loss in sporadic PD is unknown, although
it is hypothesized that aberrant protein aggregation and cellular oxidative
stress may promote DN degeneration. Homozygous mutations in DJ-1 were recently
described in two families with autosomal recessive inherited PD (Bonifati et al.
2003). In a companion article (Martinat et al. 2004), we show that mutations in
DJ-1 alter the cellular response to oxidative stress and proteasomal inhibition.
Here we show that DJ-1 functions as a redox-sensitive molecular chaperone that is
activated in an oxidative cytoplasmic environment. We further demonstrate that
DJ-1 chaperone activity in vivo extends to alpha-synuclein, a protein implicated
in PD pathogenesis.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

PMID: 15502874 [PubMed - indexed for MEDLINE]

12: PLoS Biol. 2004 Nov;2(11):e327. Epub 2004 Oct 5.

Sensitivity to oxidative stress in DJ-1-deficient dopamine neurons: an ES-
derived cell model of primary Parkinsonism.

Martinat C, Shendelman S, Jonason A, Leete T, Beal MF, Yang L, Floss T,
Abeliovich A.

Department of Pathology, Center for Neurobiology and Behavior, and Taub
Institute, Columbia University, New York, New York, USA.

The hallmark of Parkinson's disease (PD) is the selective loss of dopamine
neurons in the ventral midbrain. Although the cause of neurodegeneration in PD is
unknown, a Mendelian inheritance pattern is observed in rare cases, indicating a
genetic factor. Furthermore, pathological analyses of PD substantia nigra have
correlated cellular oxidative stress and altered proteasomal function with PD.
Homozygous mutations in DJ-1 were recently described in two families with
autosomal recessive Parkinsonism, one of which is a large deletion that is likely
to lead to loss of function. Here we show that embryonic stem cells deficient in
DJ-1 display increased sensitivity to oxidative stress and proteasomal
inhibition. The accumulation of reactive oxygen species in toxin-treated
DJ-1-deficient cells initially appears normal, but these cells are unable to cope
with the consequent damage that ultimately leads to apoptotic death. Furthermore,
we find that dopamine neurons derived from in vitro-differentiated DJ-1-deficient
embryonic stem cells display decreased survival and increased sensitivity to
oxidative stress. These data are consistent with a protective role for DJ-1, and
demonstrate the utility of genetically modified embryonic stem cell-derived
neurons as cellular models of neuronal disorders.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

PMID: 15502868 [PubMed - indexed for MEDLINE]