alpha-Synuclein aggregates interfere with Parkin solubility and distribution: role in the pathogenesis of Parkinson disease.
Parkinson disease (PD) belongs to a heterogeneous group of neurodegenerative disorders with movement alterations, cognitive impairment, and alpha-synuclein accumulation in cortical and subcortical regions. Jointly, these disorders are denominated Lewy body disease. Mutations in the parkin gene are the most common cause of familial parkinsonism, and a growing number of studies have shown that stress factors associated with sporadic PD promote parkin accumulation in the insoluble fraction. alpha-Synuclein and parkin accumulation and mutations in these genes have been associated with familial PD. To investigate whether alpha-synuclein accumulation might be involved in the pathogenesis of these disorders by interfering with parkin solubility, synuclein-transfected neuronal cells were transduced with lentiviral vectors expressing parkin. Challenging neurons with proteasome inhibitors or amyloid-beta resulted in accumulation of insoluble parkin and, to a lesser extent, alpha-tubulin. Similarly to neurons in the brains of patients with Lewy body disease, in co-transduced cells alpha-synuclein and parkin colocalized and co-immunoprecipitated. These effects resulted in decreased parkin and alpha-tubulin ubiquitination, accumulation of insoluble parkin, and cytoskeletal alterations with reduced neurite outgrowth. Taken together, accumulation of alpha-synuclein might contribute to the pathogenesis of PD and other Lewy body diseases by promoting alterations in parkin and tubulin solubility, which in turn might compromise neural function by damaging the neuronal cytoskeleton. These studies provide a new perspective on the potential nature of pathogenic alpha-synuclein and parkin interactions in Parkinson disease.
Kawahara
Kohichi
K
Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, California 92039-0624, USA.
Hashimoto
Makoto
M
Bar-On
Pazit
P
Ho
Gilbert J
GJ
Crews
Leslie
L
Mizuno
Hideya
H
Rockenstein
Edward
E
Imam
Syed Z
SZ
Masliah
Eliezer
E
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism*; D051381:Rats; D014404:Tubulin / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D051844:alpha-Synuclein / Q000378:metabolism / Q000502:physiology*; D051846:beta-Synuclein / Q000378:metabolism
D014404:Tubulin; D051844:alpha-Synuclein; D051846:beta-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein