No abstract

ATP11A translocates phosphatidylserine (PtdSer), but not phosphatidylcholine (PtdCho), from the outer to inner leaflet of plasma membranes, thereby maintaining the asymmetric distribution of PtdSer. We herein detected a de novo heterozygous point mutation in ATP11A in a patient with developmental delays and neurological deterioration. Mice carrying the corresponding mutation died perinatally or soon after birth with signs of neurological disorders. This mutation caused an amino acid substitution (Q84E) in the first transmembrane segment of ATP11A, and mutant ATP11A flipped PtdCho. Molecular dynamic simulations revealed that the mutation allowed PtdCho binding at the substrate entry site. Aberrant PtdCho flipping markedly decreased the concentration of PtdCho in the outer leaflet of plasma membranes, whereas sphingomyelin (SM) concentrations in the outer leaflet increased. This change in the distribution of phospholipids altered cell characteristics, including cell growth, cholesterol homeostasis, and sensitivity to sphingomyelinase. MALDI-imaging mass-spectrometry showed a marked increase of SM levels in the brains of Q84E knock-in mouse embryos. These results provide insights into the physiological importance of the substrate specificity of plasma membrane flippases for the proper distribution of PtdCho and SM.

Non-motor symptoms (NMS) are common among patients with Parkinson’s disease and reduce patients’ quality of life (QOL). However, there remain considerable unmet needs for NMS management. Three monoamine oxidase B inhibitors (MAO-BIs), selegiline, rasagiline, and safinamide, have become commercially available in many countries. Although an increasing number of studies have reported potential beneficial effects of MAO-BIs on QOL and NMS, there has been no consensus. Thus, the primary objective of this study was to provide an up-to-date systematic review of the QOL and NMS outcomes from the available clinical studies of MAO-BIs. We conducted a literature search using the PubMed, Scopus, and Cochrane Library databases in November 2021. We identified 60 publications relevant to this topic. Overall, rasagiline and safinamide had more published evidence on QOL and NMS changes compared with selegiline. This was likely impacted by selegiline being introduced many years prior to the field embarking on the study of NMS. The impact of MAO-BIs on QOL was inconsistent across studies, and this was unlikely to be clinically meaningful. MAO-BIs may potentially improve depression, sleep disturbances, and pain. In contrast, cognitive and olfactory dysfunctions are likely unresponsive to MAO-BIs. Given the paucity of evidence and controlled, long-term studies, the effects of MAO-BIs on fatigue, autonomic dysfunctions, apathy, and ICD remain unclear. The effects of MAO-BIs on static and fluctuating NMS have never been investigated systematically. More high-quality studies will be needed and should enable clinicians to provide personalized medicine based on a non-motor symptom profile.

Comprehensive analysis is required for the accurate diagnosis of MV2-type sporadic Creutzfeldt-Jakob disease (sCJD) because it shows a wide clinicopathological spectrum. Here, we describe the clinical findings and neuropathologic observations of an autopsy-confirmed MV2K-type sCJD case with extensive spongiform changes of the cerebral cortex. In the early disease stages, the patient exhibited gait disturbance with ataxia and gradually showed cognitive dysfunction. Diffusion-weighted magnetic resonance images revealed hyperintense regions in the cerebral cortex, basal ganglia, and particularly in the thalamus. Prion protein (PrP) gene analysis revealed no mutations, and polymorphic codon 129 exhibited methionine and valine heterozygosity. During the course of the disease, a startle reaction was observed, whereas myoclonus was not observed. Electroencephalography showed no periodic sharp wave complexes. The patient died at age 61 years with 13 months total disease duration and did not reach the akinetic mutism state. Pathologic investigation revealed extensive fine vacuole-type spongiform change in the cerebral cortex, and the appearance of vacuolation tended to be more pronounced in the deeper layers. Numerous kuru plaques were observed in the cerebellum. PrP immunostaining revealed extensive diffuse synaptic-type PrP deposition in the cerebral cortex, and the finding was prominent in the deeper layer with perineuronal-type PrP deposition. In the limbic system, basal ganglia, and thalamus, mixed small plaque-type PrP with synaptic-type PrP deposition was observed. In the cerebellar cortex, diffuse synaptic-type PrP depositions were observed with numerous strongly immunopositive plaques. Western blot analysis of examined brain samples revealed mixed type 2 PrP Sc (scrapie type) and intermediate-type PrP Sc .

Individuals with prodromal symptoms of Lewy body disease (LBD), such as rapid eye movement sleep behavior disorder (RBD), often showed imaging defects similar to patients with Parkinson’s disease and dementia with Lewy bodies. We examined dopamine transporter (DaT) single-photon-emission computed tomography (SPECT) and metaiodobenzylguanidine (MIBG) scintigraphy in 69 high-risk subjects with ≥2 prodromal symptoms (dysautonomia, hyposmia, and probable RBD) and 32 low-risk subjects without prodromal symptoms, whom were identified through a questionnaire survey of health checkup examinees. The high-risk subjects had significantly worse scores on Stroop test, line orientation test, and the Odor Stick Identification Test for Japanese than the low-risk subjects. The prevalence of abnormalities on DaT-SPECT was higher in the high-risk group than in the low-risk group (24.6% vs. 6.3%, p = 0.030). A decreased uptake on DaT-SPECT was associated with motor impairment, and MIBG scintigraphy defects were associated with hyposmia. The simultaneous evaluation of DaT-SPECT and MIBG scintigraphy may capture a wide range of individuals with prodromal LBD.