Dorfin localizes to the ubiquitylated inclusions in Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and amyotrophic lateral sclerosis.
In many neurodegenerative diseases, the cytopathological hallmark is the presence of ubiquitylated inclusions consisting of insoluble protein aggregates. Lewy bodies in Parkinson's disease and dementia with Lewy bodies disease, glial cell inclusions in multiple system atrophy, and hyaline inclusions in amyotrophic lateral sclerosis (ALS) are representative of these inclusions. The elucidation of the components of these inclusions and the mechanisms underlying inclusion formation is important in uncovering the pathogenesis of these disorders. We hypothesized that Dorfin, a perinuclearly located E3 ubiquitin ligase, participates in the formation of ubiquitylated inclusions in a wide range of neurodegenerative diseases. Here, we report that affinity-purified anti-Dorfin antibody labeled ubiquitylated inclusions of Parkinson's disease, dementia with Lewy bodies disease, multiple system atrophy, and sporadic and familial ALS. A double-immunofluorescence study revealed that Dorfin shows a distribution pattern parallel to that of ubiquitin. Furthermore, by a filter trap assay, we detected that Dorfin is present in the ubiquitylated high-molecular weight structures derived from these diseases. These results suggest that Dorfin plays a crucial role in the formation of ubiquitylated inclusions of alpha-synucleinopathy and ALS. However, because we failed to show the direct binding of alpha-synuclein with Dorfin, future investigations into the binding partner(s) of Dorfin will be needed to deepen our understanding of the pathophysiology of alpha-synucleinopathy and ALS.
Hishikawa
Nozomi
N
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Niwa
Jun-Ichi
J
Doyu
Manabu
M
Ito
Takashi
T
Ishigaki
Shinsuke
S
Hashizume
Yoshio
Y
Sobue
Gen
G
D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000906:Antibodies / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D020961:Lewy Body Disease / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008970:Molecular Weight; D019578:Multiple System Atrophy / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D051843:Synucleins; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D051844:alpha-Synuclein
D000906:Antibodies; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C000606290:SOD1 protein, human; D051843:Synucleins; D025801:Ubiquitin; D051844:alpha-Synuclein; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C423571:RNF19A protein, human; D044767:Ubiquitin-Protein Ligases