Jiro Fukae

Expression of 8-oxoguanine DNA glycosylase (OGG1) in Parkinson’s disease and related neurodegenerative disorders

Oxidative stress including DNA oxidation is implicated in Parkinson’s disease (PD). We postulated that DNA repair enzymes such as 8-oxoguanosine DNA glycosylase (OGG1) are involved in the PD process. We performed immunohistochemical and biochemical studies on brains of patients with PD and those of patients with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) as disease controls, and control subjects. We found higher expression levels of mitochondrial isoforms of OGG1 enzymes in the substantia nigra (SN) in cases of PD. Furthermore, Western blot analysis revealed high OGG1 levels in the SN of the patients with PD. Our results indicate the importance of oxidative stress within the susceptible lesions in the pathogenesis of PD.

Up-regulation of hMUTYH, a DNA repair enzyme, in the mitochondria of substantia nigra in Parkinson’s disease

There is ample evidence for the involvement of oxidative stress in mitochondrial DNA damage and repair mechanisms in Parkinson’s disease (PD). The human MutY homolog (hMUTYH) which removes misincorporated adenine opposite 8-oxoG in DNA functions in post-replication, and is localized in the nuclei and mitochondria. We hypothesized that hMUTYH is involved in the disease process of PD. To test our hypothesis, we performed immunohistochemical and biochemical studies on brains of patients with PD and those of control patients. Our results showed up-regulation of hMUTYH in the mitochondria of the SN of PD patients. Western blot analysis also revealed high hMUTYH levels in PD patients and expression of a 47-kDa molecule in the brains as the major isoform. This molecule was localized within the mitochondria as confirmed by double staining with a mitochondrial marker. To confirm the presence of this molecule, we examined the mRNAs of isoforms that translate to the 47-kDa molecule. Based on the amount of mRNAs, the major molecule was α4. Interestingly, this molecule lacks the mitochondria targeting sequence. Our results suggest that hMUTYH might be a useful marker of oxidative stress and that oxidative stress and genomic instability are important in the PD disease process.

Motor and non-motor symptoms of 1453 patients with Parkinson's disease: Prevalence and risks

PURPOSE We examined the prevalence and risk of clinical symptoms in a large number of Japanese patients with Parkinsons disease (PD) (n = 1453; 650 males). METHODS Events were analyzed using Kaplan-Meier survival curves, logistic regression, and Cox proportional-hazards models. RESULTS The mean age (SD) was 67.7 (10.0), age of onset was 58.0 (11.5), and disease duration was 9.7 (6.6) years. The mean modified Hoehn and Yahr stage was 2.8 (1.2). Most patients (88.9%) received levodopa (547.7 (257.6) mg/day). A large proportion (81.3%) received dopamine agonists (136.2 (140.7) mg/day). About 23.4% received pain treatment 6.9 (5.1) years after the onset; females (p < 0.05) and patients with late-onset PD (≥60 years, p < 0.001) were more likely to be affected. About 44.7% of patients had wearing-off 7.5 (4.7) years after the onset, and it was more common in females (p < 0.001) and patients with early-onset PD (p < 0.001). Camptocormia was found in 9.5% of patients 8.1 (6.2) years after the onset, and it was more common in females (p < 0.05) and patients with late-onset PD (p < 0.05). About 28.6% of patients developed psychosis 9.0 (5.4) years after the onset, and it was more likely to occur in patients with late-onset PD (p < 0.001). Late-onset PD and cerebrovascular disease were also associated with increased risk of pneumonia. CONCLUSIONS Considering that very few studies have assessed numerous clinical symptoms in the same report, these data provide a useful reference for the clinical course of PD.

Sweet's syndrome associated with encephalitis.

The involvement of the central nervous system (CNS) in Sweets syndrome (acute febrile neutrophilic dermatosis) is rare. We report a 47-year-old woman who presented with acute encephalitis and was subsequently diagnosed as having Sweets syndrome. She developed altered consciousness following fever and erythematous skin plaques in the extremities. Cerebrospinal fluid (CSF) examination disclosed neutrophilic pleocytosis without decreased glucose level. Brain magnetic resonance imaging (MRI) showed abnormal signal intensity lesions in the basal ganglia and the hippocampus. Skin biopsy revealed a dense dermal infiltration of neutrophils, which is compatible with Sweets syndrome. Treatment with acyclovir and antibiotics failed, but the subsequent corticosteroid therapy was effective. Awareness of neurological complication in Sweets syndrome may avoid unnecessary empiric therapy for meningoencephalitis and will lead to a successful treatment with corticosteroids.

Programmed cell death‐2 isoform1 is ubiquitinated by parkin and increased in the substantia nigra of patients with autosomal recessive Parkinson's disease

MINT‐6806000: PDCD2 (uniprotkb:Q16342) physically interacts (MI:0218) with ubiquitin (uniprotkb:P62988) by anti tag coimmunoprecipitation (MI:0007).

Positive immunoreactivity for vesicular monoamine transporter 2 in Lewy bodies and Lewy neurites in substantia nigra

Vesicular monoamine transporter 2 (VMAT2) is responsible for packing dopamine into vesicles, and reduces the effects of neurotoxins by sequestering them into vesicles. In this report, we tested the hypothesis that VMAT2 is associated with Lewy body (LB) formation by immunohistochemical staining of midbrain and cortical sections of autopsied brains of patients with Parkinsons disease (PD) and diffuse Lewy body disease (DLBD) for VMAT2 using a polyclonal antibody against VMAT2. LBs in the substantia nigra (SN) of PD and DLBD were immunoreactive for VMAT2, especially in the peripheral zone. Previous electron microscopic studies also revealed the presence of numerous dense core vesicles around the LBs, suggesting that these vesicles are related to LB formation. Indeed, the presence of a few vesicle-linked proteins such as synaptophysin and chromogranin A in LBs has been reported. Together with the low expression of VMAT2 in the SN of PD, the involvement of VMAT2 in LBs of the SN suggests the association of this protein in the neurodegeneration of nigral neurons in PD.

A Novel DCTN1 mutation with late‐onset parkinsonism and frontotemporal atrophy

Depression, parkinsonism, and hypoventilation (Perry syndrome) or familial motor neuron disease have been linked to mutations in dynactin P150Glued (DCTN1).

Successful treatment of relapsing neuro-Sweet's disease with corticosteroid and dapsone combination therapy.

Sweets disease with central nervous system involvement, tentatively named neuro-Sweets disease, has rarely been reported. Although systemic corticosteroid therapy is highly effective for neurologic symptoms in neuro-Sweets disease, relapse is common. Here, we describe the case of a 38-year-old Japanese man who presented with relapsing neuro-Sweets disease that was successfully treated with a combination of corticosteroid and dapsone. Dapsone should be considered as a therapeutic option for neuro-Sweets disease patients showing relapse.

Adult-onset Alexander disease with palatal myoclonus and intraventricular tumour

T. Hirayama, J. Fukae, K. Noda, K. Fujishima, T. Yamamoto, K. Mori, M. Maeda, N. Hattori, N. Shiroma, S. Tsurui and Y. Okuma Department of Neurology, Juntendo University Shizuoka Hospital, Shizuoka; Department of Neurosurgery, Juntendo University Shizuoka Hospital, Shizuoka; Department of Neurology, Juntendo University School of Medicine, Tokyo; Department of Pediatrics, University of the Ryukyus, Okinawa; and Department of Pediatrics, Seirei Numazu Hospital, Shizuoka, Japan

Hoarseness due to bilateral vocal cord paralysis as an initial manifestation of familial amyotrophic lateral sclerosis.

Bulbar palsy is unusual as an initial manifestation of amyotrophic lateral sclerosis (ALS), although common in the advanced stages. In terms of bulbar palsy as a presenting symptom, dysarthria and dysphagia are of common features. Hoarseness, however, is an initial symptom of ALS in only a small number of patients. We report a 43‐year‐old female with hoarseness due to bilateral vocal cord paralysis as the first manifestation of ALS. Gene analysis revealed a heterozygous missense mutation in the SOD1 gene, which resulted in an amino acid substitution of isoleucine 149 by threonine. Hoarseness can be the initial symptom of ALS. Therefore, in cases of bilateral vocal cord paralysis of unknown etiology, ALS should be taken into consideration.