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Impaired dopamine storage resulting from alpha-synuclein mutations may contribute to the pathogenesis of Parkinson's disease.

Lotharius, Julie LU and Brundin, Patrik LU (2002) In Human Molecular Genetics 11(20). p.2395-2407
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the inability to initiate, execute and control movement. Neuropathologically, there is a striking loss of dopamine-producing neurons in the substantia nigra pars compacta, accompanied by depletion of dopamine in the striatum. Most forms of PD are sporadic, though in some cases familial inheritance is observed. In the late 1990s, two mutations in the alpha-synuclein gene were linked to rare, autosomal dominant forms of PD. Previously cloned from cholinergic vesicles of the Torpedo electric ray, alpha-synuclein is highly enriched in presynaptic nerve terminals and appears to be involved in synapse maintenance and plasticity. It is expressed ubiquitously in... (More)
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the inability to initiate, execute and control movement. Neuropathologically, there is a striking loss of dopamine-producing neurons in the substantia nigra pars compacta, accompanied by depletion of dopamine in the striatum. Most forms of PD are sporadic, though in some cases familial inheritance is observed. In the late 1990s, two mutations in the alpha-synuclein gene were linked to rare, autosomal dominant forms of PD. Previously cloned from cholinergic vesicles of the Torpedo electric ray, alpha-synuclein is highly enriched in presynaptic nerve terminals and appears to be involved in synapse maintenance and plasticity. It is expressed ubiquitously in the brain, raising the important question of why dopaminergic neurons are primarily targeted in persons carrying mutations in alpha-synuclein. In this article, we review the current literature on alpha-synuclein and suggest a possible role for this protein in vesicle recycling via its regulation of phospholipase D2, its fatty acid-binding properties, or both. Exogenous application of dopamine, as well as redistribution of vesicular dopamine to the cytoplasm, can be toxic to dopaminergic neurons. Thus, impaired neurotransmitter storage arising from mutations in alpha-synuclein could lead to cytoplasmic accumulation of dopamine. The breakdown of this labile neurotransmitter in the cytoplasm could, in turn, promote oxidative stress and metabolic dysfunction, both of which have been observed in nigral tissue from PD patients. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Molecular Genetics
volume
11
issue
20
pages
2395 - 2407
publisher
Oxford University Press
external identifiers
  • wos:000178515900007
  • pmid:12351575
ISSN
0964-6906
DOI
10.1093/hmg/11.20.2395
language
English
LU publication?
yes
id
5bc3d4d6-b5aa-4621-81e7-6894af007f2b (old id 110150)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12351575&dopt=Abstract
date added to LUP
2007-07-23 15:48:48
date last changed
2016-09-30 05:39:08
@article{5bc3d4d6-b5aa-4621-81e7-6894af007f2b,
  abstract     = {Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the inability to initiate, execute and control movement. Neuropathologically, there is a striking loss of dopamine-producing neurons in the substantia nigra pars compacta, accompanied by depletion of dopamine in the striatum. Most forms of PD are sporadic, though in some cases familial inheritance is observed. In the late 1990s, two mutations in the alpha-synuclein gene were linked to rare, autosomal dominant forms of PD. Previously cloned from cholinergic vesicles of the Torpedo electric ray, alpha-synuclein is highly enriched in presynaptic nerve terminals and appears to be involved in synapse maintenance and plasticity. It is expressed ubiquitously in the brain, raising the important question of why dopaminergic neurons are primarily targeted in persons carrying mutations in alpha-synuclein. In this article, we review the current literature on alpha-synuclein and suggest a possible role for this protein in vesicle recycling via its regulation of phospholipase D2, its fatty acid-binding properties, or both. Exogenous application of dopamine, as well as redistribution of vesicular dopamine to the cytoplasm, can be toxic to dopaminergic neurons. Thus, impaired neurotransmitter storage arising from mutations in alpha-synuclein could lead to cytoplasmic accumulation of dopamine. The breakdown of this labile neurotransmitter in the cytoplasm could, in turn, promote oxidative stress and metabolic dysfunction, both of which have been observed in nigral tissue from PD patients.},
  author       = {Lotharius, Julie and Brundin, Patrik},
  issn         = {0964-6906},
  language     = {eng},
  number       = {20},
  pages        = {2395--2407},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Impaired dopamine storage resulting from alpha-synuclein mutations may contribute to the pathogenesis of Parkinson's disease.},
  url          = {http://dx.doi.org/10.1093/hmg/11.20.2395},
  volume       = {11},
  year         = {2002},
}