Impaired dopamine storage resulting from alpha-synuclein mutations may contribute to the pathogenesis of Parkinson's disease.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/110150
- author
- Lotharius, Julie LU and Brundin, Patrik LU
- organization
- publishing date
- 2002
- 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
- scopus:0036797552
- 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
- 2016-04-01 11:40:09
- date last changed
- 2022-03-28 01:20:32
@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}},
doi = {{10.1093/hmg/11.20.2395}},
volume = {{11}},
year = {{2002}},
}