Impaired dopamine storage resulting from α-synuclein mutations may contribute to the pathogenesis of Parkinson's disease
Identifieur interne : 001884 ( Main/Exploration ); précédent : 001883; suivant : 001885Impaired dopamine storage resulting from α-synuclein mutations may contribute to the pathogenesis of Parkinson's disease
Auteurs : Julie Lotharius [Suède] ; Patrik Brundin [Suède]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2002-10-01.
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 α-synuclein gene were linked to rare, autosomal dominant forms of PD. Previously cloned from cholinergic vesicles of the Torpedo electric ray, α-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 α-synuclein. In this article, we review the current literature on α-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 α-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.
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DOI: 10.1093/hmg/11.20.2395
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Mol. Genet.</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2002-10-01">2002-10-01</date><biblScope unit="volume">11</biblScope><biblScope unit="issue">20</biblScope><biblScope unit="page" from="2395">2395</biblScope><biblScope unit="page" to="2407">2407</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">5B0F2F76455317D5A5C654BD0BBDE9A3155E563B</idno><idno type="DOI">10.1093/hmg/11.20.2395</idno><idno type="local">ddf273</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 α-synuclein gene were linked to rare, autosomal dominant forms of PD. Previously cloned from cholinergic vesicles of the Torpedo electric ray, α-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 α-synuclein. In this article, we review the current literature on α-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 α-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.</div></front></TEI><affiliations><list><country><li>Suède</li></country></list><tree><country name="Suède"><noRegion><name sortKey="Lotharius, Julie" sort="Lotharius, Julie" uniqKey="Lotharius J" first="Julie" last="Lotharius">Julie Lotharius</name></noRegion><name sortKey="Brundin, Patrik" sort="Brundin, Patrik" uniqKey="Brundin P" first="Patrik" last="Brundin">Patrik Brundin</name><name sortKey="Lotharius, Julie" sort="Lotharius, Julie" uniqKey="Lotharius J" first="Julie" last="Lotharius">Julie Lotharius</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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