I started my research on Parkinson’s disease in 1991 at Juntendo University under Professor Mizuno. My main theme there was mitochondrial dysfunction of Parkinson’s disease. I discovered the phenomenon of the decreased amount of complex I in the substantia nigra of Parkinson’s disease patients.

From 1992 to 1993, I studied molecular biology at the Department of Biological Chemistry of Nagoya University. In addition, my job was cloning of 24-kDa subunit (NDFUV2) of Complex I. After cloning and elucidating the structure of this gene, I identified a single nucleotide polymorphism (snp) in this gene. I found that this snp could be a risk factor for developing Parkinson’s.

“I think that genetic-environmental interaction could be considered as a major cause for Parkinson’s disease.”

When I came back to Juntendo University in 1993, I continued to research the etiology and pathogenesis of Parkinson’s. I graduated from graduate school of Juntendo University in 1994. In 1998, we identified the disease gene for an autosomal recessive form of young onset familial Parkinson’s disease, and named the gene "parkin." This is the second form of familial Parkinson’s disease in which the disease gene was identified. Now my interest is in elucidating the pathogenesis for Parkinson’s disease by getting a hint from monogenically inherited forms of the disorder.

I am a neurologist at Juntendo University. Our university hospital has so many parkinsonian patients— probably approximately 1% of parkisonian patients among all the Japanese patients with Parkinson’s disease. Thus, I have many opportunities to treat the patients of this disease.

In addition, Parkinson’s disease is the second-most prevalent neurodegenerative disorder next to Alzheimer’s disease. Since the induction of levodopa therapy, the prognosis of this disease has been improved. But, Parkinson’s patients must continue to take this medicine their entire lives. Moreover, the disease has been considered one of the progressive diseases. In this point, I make the efforts to elucidate the true cause for this disease. This is the reason why I continue to research Parkinson’s disease—it is necessary to emphasize it.

Our group at Juntendo University has two groups: the first is the group for clinical study and the other is for basic neuroscience. But most of the members of our department of neurology, including myself, work as both clinician and scientist, simultaneously. This is a unique point for the style of the research.

We identified the causative gene responsible for autosomal recessive juvenile parkinsonism (AR-JP). The gene was named parkin. This form is the most frequent and it shows worldwide distribution. Although the age at onset is young, the clinical features are very similar to those of the common form of Parkinson’s disease. Moreover, the pathological findings generally revealed the lack of Lewy bodies, which is the hallmark of Parkinson’s disease except for a few cases.

Our findings suggest that parkin might be essential for the formation of Lewy bodies. Importantly, this gene product, parkin, is linked to the ubiquitin-proteasome pathway as an ubiquitin ligase. The ubiquitin is an important component of Lewy bodies. The discovery of its function indicated that proteolytic pathways such as ubiquitin-proteasome and autophagy-lysosomal pathway could play an important role not only for Parkinson’s disease but also other neurodegenerative disorders, such as poly-Q diseases, Alzheimer’s disease, multiple system atrophy, amyotrophic lateral sclerosis, progressive supranuclear palsy, corticobasal degeneration, and Pick disease. Most of these neurodegenerative disorders pathologically revealed the neuronal loss with intranuclear or cytoplasmic inclusions. Thus, such diseases are considered to be conformational diseases. In this point, the discovery of parkin enhances the concept of the involvement of proteolytic pathways in pathogenesis.

We mapped the locus for AR-JP to the long arm of chromosome 6 (6q25.2-q27). The young-onset Parkinson’s disease was linked strongly to the markers D6S305 and D6S253; the former was deleted in one Japanese patient. By positional cloning within this microdeletion, we have now isolated a complementary DNA done in 2,960 base pairs with a 1,395-base-pair open reading frame, encoding a protein of 465 amino acids with moderate similarity to ubiquitin at the amino terminus and a RING-finger motif at the carboxy terminus. The gene spans 1.4 Mb and consists of 12 exons, five of which (exons 3-7) are deleted in the patient. Four other AR-JP patients from three unrelated families have a deletion affecting exon 4 alone. This gene expression is ubiquitous and is abundant in the brain, including the substantia nigra. Mutations in the newly identified gene appear to be responsible for the pathogenesis of AR-JP, and we have therefore named the protein product parkin.

I think that genetic-environmental interaction could be considered as a major cause for Parkinson’s disease. Genetic factors in particular could contribute to the pathogenesis of Parkinson’s disease. In contrast, most of the patients with Parkinson’s disease have sporadic, not monogenically inherited forms of Parkinson’s disease. But, the patients with Parkinson’s disease are heterogeneous. If we elucidate the pathogenesis of nigral degeneration that is responsive to levodopa therapy, the gene screening provides us good information. Indeed, seven causative genes for monogenically inherited forms have been identified.

In contrast, three causative genes for the familial Alzheimer’s disease have been identified. Of course, more genes might be involved in the cause for Alzheimer’s disease, and more genes could play roles for familial Parkinson’s disease. Therefore, it is important to screen the known genes for familial Parkinson’s disease and we would identify a novel causative gene for familial Parkinson’s disease with no mutations in the known genes.

Considering the etiology of Parkinson’s disease, it is necessary to find out a specific biomarker for diagnosis. In addition, if we can identify the neuroprotective therapies, how we identify subclinical state is very important. Recently, REM-sleep behavior disorder (RBD) and olfactory dysfunction might be an early sign for the development of Parkinson’s.

Thus, my research for other aspects of Parkinson’s disease aims to detect the subclinical state including a biomarker. Of course, it is mandatory to elucidate the true cause for Parkinson’s disease. I would like to research everything including the basic and clinical sciences. Finally, I would like to create a new drug that prevents the progression of the disease.

I think that it is very important to elucidate the true mechanisms of nigral degeneration. Since the induction of levodopa, the prognosis has been improved now. But, considering the quality of life, we should discover a new drug that has potentials for neuroprotection. As I mentioned above, Parkinson’s disease is heterogeneous. Thus, it is a powerful approach to elucidate the function of familial Parkinson’s disease gene products such as parkin, alpha-synuclein, PINK1, DJ-1, and LRRK2. I think that all the gene products could share a common pathway. Therefore, the field of familial Parkinson’s disease is a center of my research.