Cytosolic catechols inhibit alpha-synuclein aggregation and facilitate the formation of intracellular soluble oligomeric intermediates.
Aberrant aggregation of alpha-synuclein (alpha-syn) to form fibrils and insoluble aggregates has been implicated in the pathogenic processes of many neurodegenerative diseases. Despite the dramatic effects of dopamine in inhibiting the formation of alpha-syn fibrils by stabilization of oligomeric intermediates in cell-free systems, no studies have examined the effects of intracellular dopamine on alpha-syn aggregation. To study this process and its association with neurodegeneration, intracellular catechol levels were increased to various levels by expressing different forms of tyrosine hydroxylase, in cells induced to form alpha-syn aggregates. The increase in the steady-state dopamine levels inhibited the formation of alpha-syn aggregates and induced the formation of innocuous oligomeric intermediates. Analysis of transgenic mice expressing the disease-associated A53T mutant alpha-syn revealed the presence of oligomeric alpha-syn in nondegenerating dopaminergic neurons that do contain insoluble alpha-syn. These data indicate that intraneuronal dopamine levels can be a major modulator of alpha-syn aggregation and inclusion formation, with important implications on the selective degeneration of these neurons in Parkinson's disease.
Mazzulli
Joseph R
JR
The Joseph Stokes Jr. Research Institute, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Mishizen
Amanda J
AJ
Giasson
Benoit I
BI
Lynch
David R
DR
Thomas
Steven A
SA
Nakashima
Akira
A
Nagatsu
Toshiharu
T
Ota
Akira
A
Ischiropoulos
Harry
H
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D019943:Amino Acid Substitution; D000818:Animals; D002396:Catechols / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor / Q000737:chemistry; D002540:Cerebral Cortex / Q000737:chemistry; D003342:Corpus Striatum / Q000737:chemistry; D003600:Cytosol / Q000737:chemistry*; D004298:Dopamine / Q000502:physiology*; D006801:Humans; D007980:Levodopa / Q000032:analysis; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009447:Neuroblastoma / Q000473:pathology; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000378:metabolism; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000502:physiology; D012995:Solubility; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000502:physiology; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics
D002396:Catechols; D011993:Recombinant Fusion Proteins; D051844:alpha-Synuclein; D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; D014212:Tretinoin; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine