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(American Journal of Pathology. 2003;163:609-619.)
© 2003 American Society for Investigative Pathology

Dorfin Localizes to the Ubiquitylated Inclusions in Parkinson’s Disease, Dementia with Lewy Bodies, Multiple System Atrophy, and Amyotrophic Lateral Sclerosis

Nozomi Hishikawa^*, Jun-ichi Niwa^*, Manabu Doyu^*, Takashi Ito^*, Shinsuke Ishigaki^*, Yoshio Hashizume and Gen Sobue^*

From the Department of Neurology,^* Nagoya University Graduate School of Medicine, Nagoya; and the Department of Neuropathology, Institute for Medical Sciences of Aging, Aichi Medical University, Aichi, Japan

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 -synucleinopathy and ALS. However, because we failed to show the direct binding of -synuclein with Dorfin, future investigations into the binding partner(s) of Dorfin will be needed to deepen our understanding of the pathophysiology of -synucleinopathy and ALS.

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