Phosphorylation of α-synuclein at T64 results in distinct oligomers and exerts toxicity in models of Parkinson's disease.

α-Synuclein accumulates in Lewy bodies, and this accumulation is a pathological hallmark of Parkinson's disease (PD). Previous studies have indicated a causal role of α-synuclein in the pathogenesis of PD. However, the molecular and cellular mechanisms of α-synuclein toxicity remain elusive. Here, we describe a novel phosphorylation site of α-synuclein at T64 and the detailed characteristics of this post-translational modification. T64 phosphorylation was enhanced in both PD models and human PD brains. T64D phosphomimetic mutation led to distinct oligomer formation, and the structure of the oligomer was similar to that of α-synuclein oligomer with A53T mutation. Such phosphomimetic mutation induced mitochondrial dysfunction, lysosomal disorder, and cell death in cells and neurodegeneration in vivo, indicating a pathogenic role of α-synuclein phosphorylation at T64 in PD.

[The questionnaire survey regarding the impact of COVID-19 pandemic on Parkinson's disease patients].

We conducted the multicenter questionnaire survey targeting patients with Parkinson's disease (PD) in order to investigate the impacts on their daily lives and their requests to hospitals in the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Mainly using open-ended questionnaire, we asked their anxiety, troubles they are facing, and requests toward hospitals in the pandemic of SARS-CoV-2. Two hundred fifth-eight PD patients answered the questionnaire. There were various opinions about anxiety such as "PD patients are susceptible and vulnerable to SARS-CoV-2" (36.8%). Concerning the troubles in the pandemic, the most frequent answer was that they couldn't participate in the rehabilitation and elderly day care (38.4%). Relatively many PD patients requested telemedicine (29.5%), whereas some people hoped face-to-face medical care (8.1%). There were demands about the delivery of medications (50.0%), the establishment of telephone consultations (43.8%), resources for rehabilitation at home (43.8%). The medical care adapted to the anxiety, trouble and requests of PD patients will be required in the era when we have to live with SARS-CoV-2.

Parkinson's disease with a typical clinical course of 17 years overlapped by Creutzfeldt-Jakob disease: an autopsy case report.

BACKGROUND: Late-stage Parkinson's disease (PD) often presents with neuropsychiatric symptoms such as dementia, psychosis, excessive daytime sleepiness, apathy, depression, and anxiety. However, neuropsychiatric symptoms are the cardinal features of Creutzfeldt-Jakob disease (CJD), raising the possibility that CJD may be an overlooked condition when it accompanies late-stage PD. CASE PRESENTATION: We describe a female autopsy case of PD with a typical clinical course of 17 years, in which CJD overlapped with PD during the final year of the patient's life. The patient died aged 85 years. Neuropathological features included widespread Lewy body-related α-synucleinopathy predominantly in the brainstem and limbic system, as well as the typical pathology of methionine/methionine type 1 CJD in the brain. CONCLUSIONS: Our case demonstrates the clinicopathological co-occurrence of PD and CJD in a sporadic patient. The possibility of mixed pathology, including prion pathology, should be taken into account when neuropsychiatric symptoms are noted during the disease course of PD.

What can we learn from the effect of trihexyphenidyl on motor fluctuations during continuous levodopa-carbidopa intestinal gel infusion (LCIG)? - First documented case.

Motor fluctuations can be seen even during treatment with continuous levodopa-carbidopa intestinal gel infusion (LCIG). We report on a middle-aged man with advanced Parkinson's disease (PD) on LCIG in which motor fluctuations have been improved with an anticholinergic. To the best of our knowledge, there have been no previous LCIG cases reported with motor fluctuations responding to non-dopaminergic agent, which might reveal some clues to its pathophysiology. Long-term oral levodopa treatment is associated with development of potentially disabling motor complications including motor fluctuations and dyskinesias in the majority of patients with PD. It has been suggested that motor complications are related to the nonphysiological restoration of brain dopamine with intermittent administration of standard oral levodopa. LCIG significantly reduces "off" time and increases "on" time without dyskinesia in comparison to standard oral levodopa through consistent plasma concentration of levodopa to restore brain dopamine in a more physiological manner. However, it has been reported that PD patients on LCIG often worsen during the afternoon hours, even with stable plasma concentration of levodopa. This raises the possibility that additional factors to dopamine deficiency could play a role in occurrence of motor fluctuations. Here we offer a hypothesis that altered cholinergic signaling could also be involved in the pathophysiology of motor fluctuations, based on our clinical evidence that anticholinergic drug has eliminated motor fluctuations during LCIG in a patient with PD. Further studies for non-dopaminergic along with dopaminergic signaling may be needed to better understand the pathophysiological basis of motor complications in PD.

Parkinson's disease-associated iPLA2-VIA/PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling.

Mutations in the iPLA2-VIA/PLA2G6 gene are responsible for PARK14-linked Parkinson's disease (PD) with α-synucleinopathy. However, it is unclear how iPLA2-VIA mutations lead to α-synuclein (α-Syn) aggregation and dopaminergic (DA) neurodegeneration. Here, we report that iPLA2-VIA-deficient Drosophila exhibits defects in neurotransmission during early developmental stages and progressive cell loss throughout the brain, including degeneration of the DA neurons. Lipid analysis of brain tissues reveals that the acyl-chain length of phospholipids is shortened by iPLA2-VIA loss, which causes endoplasmic reticulum (ER) stress through membrane lipid disequilibrium. The introduction of wild-type human iPLA2-VIA or the mitochondria-ER contact site-resident protein C19orf12 in iPLA2-VIA-deficient flies rescues the phenotypes associated with altered lipid composition, ER stress, and DA neurodegeneration, whereas the introduction of a disease-associated missense mutant, iPLA2-VIA A80T, fails to suppress these phenotypes. The acceleration of α-Syn aggregation by iPLA2-VIA loss is suppressed by the administration of linoleic acid, correcting the brain lipid composition. Our findings suggest that membrane remodeling by iPLA2-VIA is required for the survival of DA neurons and α-Syn stability.

Arylsulfatase A, a genetic modifier of Parkinson's disease, is an α-synuclein chaperone.

Mutations in lysosomal genes increase the risk of neurodegenerative diseases, as is the case for Parkinson's disease. Here, we found that pathogenic and protective mutations in arylsulfatase A (ARSA), a gene responsible for metachromatic leukodystrophy, a lysosomal storage disorder, are linked to Parkinson's disease. Plasma ARSA protein levels were changed in Parkinson's disease patients. ARSA deficiency caused increases in α-synuclein aggregation and secretion, and increases in α-synuclein propagation in cells and nematodes. Despite being a lysosomal protein, ARSA directly interacts with α-synuclein in the cytosol. The interaction was more extensive with protective ARSA variant and less with pathogenic ARSA variant than wild-type. ARSA inhibited the in vitro fibrillation of α-synuclein in a dose-dependent manner. Ectopic expression of ARSA reversed the α-synuclein phenotypes in both cell and fly models of synucleinopathy, the effects correlating with the extent of the physical interaction between these molecules. Collectively, these results suggest that ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein.

Anhedonia and its correlation with clinical aspects in Parkinson's disease.

Anhedonia is one of the non-motor symptoms observed in the Parkinson's disease (PD). However, there is no clear relationship between anhedonia and its correlation with other symptoms of PD. The aim of this study is to evaluate the characteristics of anhedonia and its correlation with clinical aspects of PD in a relatively large cohort. We enrolled 318 patients with PD and 62 control subjects for this study. Patients and subjects were tested using the Snaith-Hamilton Pleasure Scale Japanese version and the Beck Depression Inventory 2nd edition for the assessment of anhedonia and depression. We also investigated the correlation among clinical aspects of PD, anhedonia, and depression in patients with PD. The Snaith-Hamilton Pleasure Scale Japanese version and the Beck Depression Inventory 2nd edition scores were significantly higher in patients with PD than in control subjects (p=0.03 and p=0.0006, respectively). All PD patients with anhedonia had a significantly higher score on the unified Parkinson's disease rating scale (UPDRS) parts I and II compared to PD patients without anhedonia. Additionally, all PD patients with depression scored significantly higher on UPDRS part I-IV than PD patients without depression. The patients with anhedonia and without depression had mild motor severity and their treatment was relatively low dosage. These results suggest that anhedonia and depression are slightly linked, but not the same. PD patients with only anhedonia may be closely linked apathy found in untreated early stages of PD.

A Japanese multicenter survey characterizing pain in Parkinson's disease.

BACKGROUND: Pain is a frequent, troublesome symptom of PD but is under-recognized and poorly understood. AIM: We characterized pain prevalence, severity, and location in PD, to better understand its pathophysiology and improve diagnosis and treatment. SUBJECTS AND METHODS: A cross-sectional controlled study was conducted at 19 centers across Japan. A total of 632 subjects with Mini-Mental State Examination scores ≥24 were enrolled, including 324 PD patients and 308 controls. Sex and mean age did not differ between the two groups. Demographic and clinical data were collected. Pain was assessed using questionnaires, the SF-36v2 bodily pain scale, and a body illustration for patients to indicate the location of pain in 45 anatomical areas. RESULTS: Pain prevalence in the PD group was 78.6%, significantly higher than in controls (49.0%), as was its severity. There was no correlation between SF-36v2 score and motor scores, such as Unified Parkinson's Disease Rating Scale III or Hoehn & Yahr scores. Pain distribution was similar between groups, predominantly in the lower back, followed by the gluteal region, lower legs, thighs, posterior neck, and shoulders. CONCLUSION: Pain is a significant problem in the Japanese PD population and we discuss its pathophysiology.

Membrane lipids as therapeutic targets for Parkinson's disease: a possible link between Lewy pathology and membrane lipids.

INTRODUCTION: Pathologically, Parkinson's disease (PD) is characterized by nigral cell loss and Lewy pathology in the remaining neurons. Whereas the motor symptoms of PD show a marked response to dopamine replacement therapy, many of the non-motor symptoms are resistant to treatment. This suggests that in addition to nigral cell loss, widespread Lewy pathology in the nervous system is associated with the manifestations of PD. Areas covered: Although the mechanism of Lewy body formation remains largely unknown, it is becoming clear that changes in the behavior of α-synuclein are critical in this process. α-Synuclein behaves differently depending on the lipid composition of membranes with which it interacts; therefore, one can postulate that the altered lipid composition of neuronal membranes may lead to Lewy pathology. The lipid composition of cellular membranes is consistently altered in the brains of patients with PD, and Lewy pathology is a common feature of several human lipidoses with mutations in enzymes that affect membrane lipids. This further supports the concept that alterations in the membrane lipids of neurons are central to Lewy pathology. Expert opinion: This concept provides a new platform to establish models for the development of novel treatments for PD.

A Randomized Controlled Trial of Subcutaneous Apomorphine for Parkinson Disease: A Repeat Dose and Pharmacokinetic Study.

OBJECTIVES: This study is the first controlled trial to evaluate the efficacy and safety of subcutaneous apomorphine in Japanese patients with advanced Parkinson disease. METHODS: A phase II, multicenter, randomized, double-blind, parallel-group trial was undertaken in 16 patients with advanced Parkinson disease with wearing-off phenomenon to compare subcutaneous apomorphine versus placebo. The maintenance dose of apomorphine (1-6 mg per dose), determined individually for each patient by titration, was additionally administered 3 times at 2-hour intervals in the multiple-dose phase in which pharmacokinetics was evaluated. RESULTS: The mean (SD) maintenance apomorphine dose was 3.4 (1.4) mg (range, 2-6 mg). The change in the Unified Parkinson's Disease Rating Scale motor score 20 minutes after maintenance dose administration was significantly greater in the apomorphine group than in the placebo group (least squares mean, -24.0 vs -4.1, P = 0.021). Apomorphine treatment resulted in an "on" state approximately 20 minutes after dose administration, lasting for approximately 60 minutes. Apomorphine was rapidly absorbed, with the maximum plasma concentration (Cmax) reached in 0.367 to 0.383 hour. It was quickly eliminated with a half-life of 0.520 to 0.793 hour, suggesting no accumulation during multiple-dose phase. The Cmax of apomorphine at effective dose was presumed to be approximately 20 ng/mL. Apomorphine was well tolerated. CONCLUSIONS: Subcutaneous apomorphine is expected to provide a new treatment option in Japan as a rescue therapy. Two-hour interval injections did not cause reduced responses, and effective blood concentration was presumed to be approximately 20 ng/mL similar, to the previous study conducted at North America.

Lipid rafts involvement in the pathogenesis of Parkinson's disease.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases affecting an increasing number of people worldwide with the aging society. Although the etiology of PD remains largely unknown, it is now clear that genetic factors contribute to the pathogenesis of the disease. Recently, several causative genes have been identified in mendelian forms of PD. Growing evidence indicates that their gene products play important roles in oxidative stress response, mitochondrial function, and the ubiquitin-proteasome system, which are also implicated in idiopathic PD, suggesting that these gene products share a common pathway to nigral degeneration in both familial and idiopathic PD. Interestingly, several lines of evidence show that the gene products associate with lipid rafts which are thought to be involved in important cellular functions such as membrane trafficking, signal transduction, and cytoskeletal organization. Lipid rafts are cholesterol- and sphingolipid-enriched microdomains on the cell membranes that provide a highly saturated and viscous physicochemical microenvironment to promote protein lipid and protein protein interactions. In this article, we will review studies focusing on PD in association with lipid rafts and discuss implication of lipid rafts in the pathogenesis of PD.

Identification of a Japanese family with LRRK2 p.R1441G-related Parkinson's disease.

Leucine-rich repeat kinase 2 (LRRK2) is a causative gene of autosomal dominant familial Parkinson's disease (PD). We screened for LRRK2 mutations in 3 frequently reported exons (31, 41, and 48) in our cohort of 871 Japanese patients with PD (430 with sporadic PD and 441 probands with familial PD). Direct sequencing analysis of LRRK2 revealed 1 proband (0.11%) with a p.R1441G mutation, identified for the first time in Asian countries, besides frequently reported substitutions including, the p.G2019S mutation (0.11%) and p.G2385R variant (11.37%). Several studies have suggested that the LRRK2 p.R1441G mutation, which is highly prevalent in the Basque country, is extremely rare outside of northern Spain. Further analysis of family members of the proband with the p.R1441G mutation revealed that her mother and first cousin shared the same mutation and parkinsonism. Haplotype analysis revealed a different haplotype from that of the original Spanish families. Our patients demonstrated levodopa-responsive parkinsonism with intrafamilial clinical heterogeneity. This is the first report of familial PD because of the LRRK2 p.R1441G mutation in Asia.

Rhinorrhea in Parkinson's disease: a consecutive multicenter study in Japan.

Recent reports suggest that rhinorrhea, defined as the presence of a runny nose unrelated to respiratory infections, allergies, or sinus problems, occurs more frequently among patients with Parkinson's disease (PD) than among healthy controls. We conducted a questionnaire survey in a multicenter study throughout Japan and compared the frequency of rhinorrhea between 231 PD and 187 normal control (NC) subjects. After excluding patients with rhinitis or paranasal sinusitis, a total of 159 PD and 59 NC subjects were included in our analysis. Rhinorrhea occurred more frequently in PD patients than NC subjects (33.3% vs. 11.9%; P=0.01). Among PD patients, rhinorrhea was more common in men than women (P=0.005). Rhinorrhea was not correlated with disease duration, modified Hoehn and Yahr score, disease type (akinesia rigidity vs. tremor dominant), or cardiac sympathetic function (evaluated by (123)I-metaiodobenzylguanidine uptake). To our knowledge, this is the first multicenter study on the frequency of PD-related rhinorrhea in Asian countries.

Effects of donepezil dose escalation in Parkinson's patients with dementia receiving long-term donepezil treatment: an exploratory study.

BACKGROUND: The benefits of escalating the dose of donepezil in patients who are already receiving long-term treatment with it have not been well evaluated. Therefore, an exploratory study to assess the effects of donepezil dose escalation in patients with Parkinson's disease with dementia, and specifically on patients receiving long-term treatment with donepezil, was performed. METHODS: Patients treated with 5-mg/day donepezil for at least 3 months and having a Mini-Mental State Examination (MMSE) score between 10 and 26 were included in this study. Donepezil dosage was then increased to 10 mg/day for 12 weeks. The outcome measures were a modified form of the Neuropsychiatric Inventory (NPI) with an extra domain for additional evaluation of fluctuation in cognitive functions (NPI-11) and the MMSE. RESULTS: Of the nine patients enrolled, two withdrew because of nausea and inability to be assessed on the predetermined date; this left seven participants (four men and three women) with a mean age of 74.6 ± 6.9 years, a mean period of Parkinson's disease of 11.7 ± 7.5 years, and median donepezil use of 7 months (range: 3-56 months). At baseline, the mean total NPI-11 and mean MMSE scores were 18.3 ± 5.6 points and 21.3 ± 5.3 points, respectively. At week 12, they improved by 8.3 points (P < 0.01) and 3.0 points (P = 0.08), respectively, from the baseline. The NPI symptom domains that improved by 1 or more points were hallucination (1.3 points), depression (1.0 points), anxiety (1.6 points), and aberrant motor behaviour (1.7 points). None of the patients withdrew because of worsening of parkinsonism. CONCLUSIONS: The present results suggest that treatment with dose escalation of donepezil from 5 mg/day to 10 mg/day may be therapeutically useful for patients with Parkinson's disease with dementia who have taken donepezil 5 mg/day in the long term.

Can parkin be a target for future treatment of Parkinson's disease?

INTRODUCTION: Parkinson's disease (PD) is one of the most common neurodegenerative diseases affecting an increasing number of people worldwide with the ageing society. Although the etiology of PD remains largely unknown, it is now clear that genetic factors contribute to the pathogenesis of the disease. Recently, several causative genes have been identified in mendelian forms of PD. Growing evidence indicates that their gene products play important roles in oxidative stress response, mitochondrial function, and the ubiquitin-proteasome system, which are also implicated in idiopathic PD, suggesting that these gene products share a common pathway to nigral degeneration in both familial and idiopathic PD. However, treatment options are currently limited. AREAS COVERED: Recently, a possible role of parkin, a gene product of PARK2-liked PD, in neuroprotection has been suggested. To this regard, several investigations have focused on the possible contribution of parkin in neurotoxic insults. In this article, the role of parkin in the pathogenesis of PD and the potential of parkin as a therapeutic target in PD will be discussed. EXPERT OPINION: There is an urgent need to develop novel therapeutic options to better manage patients with PD. The data discussed in this article provide rationale for parkin as a therapeutic target.

Bilateral facial nerve palsy due to otitis media associated with myeloperoxidase-antineutrophil cytoplasmic antibody.

Otitis media (OM) is well known as a common feature of proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA)-related Wegener granulomatosis, but is a very rare condition in myeloperoxidase ANCA (MPO-ANCA)-related vasculitis. In addition, there have been a few reports showing an association of MPO-ANCA-positive OM with cranial polyneuropathy. In this report, we describe 2 patients with bilateral facial nerve palsy due to MPO-ANCA-related OM. One patient also had bilateral trigeminal neuropathy, pachymeningitis and MPO-ANCA-related glomerulonephritis, whereas the other showed isolated bilateral facial nerve palsy with OM. In both the patients, treatment with prednisolone and immune-suppressant drugs resulted in an improvement of OM and cranial polyneuropathy. Physicians should be aware that MPO-ANCA-positive OM can cause bilateral facial nerve palsy.

Evaluation of the efficacy of pramipexole for treating levodopa-induced dyskinesia in patients with Parkinson's disease.

OBJECTIVE: The long-term use of levodopa to treat Parkinson's disease (PD) is often limited by the development of motor complications (e.g., levodopa-induced dyskinesia, LID). We hypothesized that a non-ergot dopamine agonist with strong affinity for D3) dopamine receptors (pramipexole) may improve LID in patients taking an ergot D1/D2 dopamine agonist. METHODS: Patients with PD and LID being treated with levodopa in addition to an ergot dopamine agonist were randomized to either a group in which pramipexole was added to current medications or a group in which the ergot dopamine agonist was switched to pramipexole. Dyskinesia was evaluated using Core Assessment Program for Surgical Interventional Therapies scores. The unified Parkinson's disease rating scale scores, modified Hoehn and Yahr stages (at 'on' time), Parkinson's disease questionnaire-39 scores and clinical global impression-improvement scores were also used for evaluation. RESULTS: At 24 weeks, pramipexole alleviated LID with more efficiency in the switch group. CONCLUSION: Pramipexole may be a therapeutic option for treating LID because its effects on D3 dopamine receptors may balance the D1 dopamine receptor supersensitivity associated with LID.