Manabu Funayama

This study reveals that perlecan, a basement membrane proteoglycan, regulates exercise-induced vascular adaptations and isoform-specific expression of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) in skeletal muscle. Perlecan-deficient muscle exhibited enhanced levels of alternative promoter-driven PGC-1α isoforms, upregulation of angiogenic genes following acute exercise, and increased baseline and exercise-induced capillary density. These findings demonstrate that basement membrane extracellular matrix composition is associated with exercise-induced muscle-vascular cross talk, identifying perlecan as a candidate regulator of exercise training adaptations.

Pathogenic variants in the colony-stimulating factor 1 receptor (CSF1R) gene cause CSF1R-related disorder (CSF1R-RD), which encompasses a broad phenotypic spectrum including a classical adult-onset leukoencephalopathy phenotype. Within this spectrum, considerable phenotypic heterogeneity has been increasingly recognized. The pathogenic missense variant c.2539G>A has been reported in a small number of patients with CSF1R-associated leukoencephalopathy; however, its associated clinical spectrum remains incompletely characterized. To characterize the clinical spectrum associated with the CSF1R c.2539G>A pathogenic variant in a Japanese family with CSF1R-RD. Clinical evaluations and genetic analyses, including whole-exome sequencing and Sanger sequencing, were performed in available family members. We detected the same heterozygous CSF1R c.2539G>A pathogenic variant in four members from a Japanese family. Two affected individuals presented with parkinsonism, cognitive decline, and white matter abnormalities typical of CSF1R-RD, whereas the other affected individual exhibited a phenotype consistent with typical Parkinson’s disease (PD), without apparent cognitive impairment or radiological white matter abnormalities. The fourth individual initially had no overt neurological symptoms despite white matter changes on MRI and subsequently developed spastic gait with pyramidal signs, indicating intrafamilial phenotypic variability. These findings broaden the phenotypic spectrum associated with the CSF1R c.2539G>A pathogenic variant and highlight marked intrafamilial phenotypic heterogeneity, including a PD-like phenotype without typical cognitive or white matter abnormalities.

Variants in the valosin‐containing protein (VCP) gene cause multisystem proteinopathy, typically characterized by TDP‐43 pathology. However, there are few reports describing tau pathology in VCP variant carriers. Here, we report a Japanese woman carrying a heterozygous VCP R191Q variant, who developed progressive muscle weakness, frontotemporal dementia, and parkinsonism beginning in her mid‐forties and died at the age of 61. Neuropathological examination demonstrated FTLD‐TDP type D pathology involving the frontal and temporal cortices, limbic structures, brainstem, spinal cord, and skeletal muscle. In addition, a distinct pattern of tau pathology was identified, predominantly in astrocytes and extending from the lower brainstem throughout the spinal cord. Tau aggregates were distributed in perivascular, subpial, and central gray matter, with a rostrocaudal distribution. Immunohistochemistry and confocal microscopy demonstrated colocalization of 3‐repeat (3R) and 4‐repeat (4R) tau within astrocytes, with predominance of 3R tau. Western blot analysis confirmed these findings and showed a tau banding pattern similar to that in Alzheimer's disease. These features differ from those observed in disorders with astrocytic tau pathology, such as cervical spondylotic myelopathy, chronic traumatic encephalopathy, and aging‐related tau astrogliopathy, which are typically characterized by predominance of 4R tau and minimal or absent 3R tau involvement. They also differ from the neuronal tau pathology observed in the frontotemporal cortex in patients with the VCP D395G variant. This case expands the neuropathological spectrum of VCP‐related diseases and suggests a possible association between VCP variants and pathological tau aggregation.

Hemizygous variants in B-cell receptor–associated protein 31 (BCAP31) can cause deafness, dystonia, and cerebral hypomyelination syndrome, which typically presents in infancy. We performed whole-exome sequencing in a family with 2 affected individuals who exhibited congenital hearing loss and adult-onset motor symptoms, including Parkinson disease (PD) and cerebellar ataxia. To assess the frequency of BCAP31 variants, we analyzed 234 Japanese individuals with either recessively inherited familial PD or early-onset PD using Sanger sequencing. Whole-exome sequencing identified a novel BCAP31 variant (c.302G>A; p.Arg101Lys) shared by both individuals. The proband developed parkinsonism in early adulthood; responded well to levodopa; and later exhibited wearing-off phenomena, dyskinesias, and cerebellar signs. Sanger sequencing of a Japanese population with PD identified 3 additional BCAP31 variants; however, all 3 variants were predicted to be benign and showed no enrichment compared with public databases. This report links a BCAP31 variant to adult-onset PD. Our findings suggest that BCAP31 should be considered in male patients with early-onset PD and atypical features such as congenital deafness and cerebellar involvement.

Introduction: Aged non-human primates have been reported to develop tau pathology; however, most studies lack evidence of any associated neurological symptoms. To determine whether spontaneous tauopathy in cynomolgus macaques manifests with neurological symptoms, we evaluated a symptomatic aged monkey (Monkey T) alongside an asymptomatic control (Monkey A). Methods: Two male cynomolgus macaques, aged 33–34 years old at the time of necropsy, were examined. They were evaluated using comprehensive behavioral, pathological, and genetic analyses. Results: Monkey T exhibited progressive neurological symptoms for approximately two years prior to euthanasia, including tremors, nuchal dystonia, and a flexed posture, whereas Monkey A showed no abnormalities. Monkey T demonstrated persistent tremors (6.9 ± 0.7 Hz) and reduced daily motor activity, with modest improvement following L-DOPA administration. Neuropathological evaluation revealed brainstem atrophy and mild depigmentation of the substantia nigra and locus coeruleus. Extensive phosphorylated tau accumulation was observed throughout the brainstem tegmentum, including neurofibrillary tangles, threads, coiled bodies, and astrocytic inclusions. All tau lesions were positive for 4-repeat tau and negative for 3-repeat tau. MAPT sequencing identified four non-pathogenic 3′UTR variants differing between the two monkeys. Isoform analysis showed balanced 3R/4R tau expression in Monkey A but an approximately 1.3-fold increase in 4R tau in Monkey T. Discussion: The parkinsonian symptoms observed in Monkey T were more likely attributable to widespread tau pathology in the brainstem rather than overt degeneration of the nigrostriatal dopaminergic system. This case represents a rare instance of spontaneous tauopathy in an aged cynomolgus macaque, a condition that is extremely difficult to reproduce experimentally. These findings highlight the potential value of cynomolgus macaques as a relevant model for studying sporadic tauopathies, including tau seeding mechanisms.

Background: Deep brain stimulation (DBS) is effective for Parkinson's disease (PD); however, its efficacy varies with genetic background, such as the GBA1 variant—the causative gene of Gaucher disease—associated with increased PD risk and cognitive decline after subthalamic nucleus (STN)‐DBS. Objectives: The aim of the study was to examine the relationship between outcomes after STN‐DBS and GBA1 variants in PD patients undergoing bilateral STN‐DBS. Methods: Patients were retrospectively analyzed over 5 years, with clinical and genetic assessments, including GBA1 variant status performed at baseline and at 1‐, 3‐, and 5‐years post‐DBS. Longitudinal changes in motor, cognitive, and medication outcomes were evaluated using propensity score matching and linear mixed‐effects models. Results: A total of 371 PD patients undergoing bilateral STN‐DBS were analyzed, including 54 GBA1 variant carriers and 253 noncarriers, after excluding other genetic variants. Propensity score matching yielded 2 groups with balanced baseline characteristics, with 50 patients each. Over time, no significant differences were observed in motor, cognitive, or neuropsychiatric assessments between groups. GBA1 carriers exhibited worsened medication OFF‐DBS off state motor symptoms at 5 years postoperatively, whereas cognitive function, assessed by the Mini‐Mental State Examination, remained stable in both groups. Levodopa‐equivalent daily dose (LEDD) significantly decreased in both groups. Linear mixed‐effects models showed progressive motor and cognitive decline and reduced medication use over 5 years, with no significant impact on GBA1 variant status. Conclusions: Findings from Japan's largest genetic cohort suggest that GBA1 variants may not significantly affect postoperative motor or cognitive trajectories following STN‐DBS. Further validation through large‐scale multinational and multicenter studies is warranted.

Common and rare variants in LRRK2 influence Parkinson’s disease (PD) risk across diverse populations. We investigated the p.A419V variant across multiple ancestry cohorts comprising over 200,000 individuals. In cases of East Asian ancestry, the variant was significantly associated with increased risk (OR = 2.9; 95% CI: 1.66–5.10; p = 0.0002), It lies on rare EAS haplotypes, and was not in linkage disequilibrium with other LRRK2 coding variants. Although not significant, meta-analysis of age of onset in EAS cases show a suggestive trend (β = –0.89 years; SE = 1.01; p = 0.380). LRRK2 protein modelling prediction indicated that binding sites for RAB8A, RAB10, RAB29 were in close proximity to the p.A419V variant within the ARM domain. Together, these findings confirm the p.A419V as a significant PD risk factor in EAS populations, as well as highlight disease-relevant variants in the ARM domain and the link with LRRK2-RAB signaling pathway.

Background: With third-generation long-read sequencing (LRS) platforms and optical genome mapping technologies (OGM), the ability to detect large and complex structural variants (SVs) is rapidly advancing. This has led to the discovery of novel pathogenic variants, such as large deletions and insertions, in neurodegenerative movement disorders. Thus, we aimed to systematically examine the applicability of the combined application of LRS and OGM in Parkinson’s disease (PD). Methods: Ultra-high molecular weight DNA was derived from blood and fibroblast cultures and used for Oxford Nanopore Technologies (ONT) LRS and OGM. We included 19 patients with mostly early-onset PD. Variant calling was performed with the tools Sniffles2 and Spectre for ONT and the Bionano Solve software for OGM. The size distribution of deletions and insertions was compared, and a subsequent analysis pipeline based on AnnotSV, SVAFotate, and needLR was employed to annotate and filter for rare (population allele frequency ≤1%) or potentially pathogenic (CADD-SV >20) variants affecting 134 known movement disorder genes. Results: Both methods identified SVs ≥50 kb; however, OGM detected fewer SVs (49,677) with a larger mean size of 25 kb (SD=209 kb) compared to ONT (92,030, mean=17 kb, SD=1.1 Mb). In the size bracket of 50-80 kb, which falls outside the ideal detection range of Sniffles2 and Spectre, OGM detected 384 deletions and insertions, compared to six detected by ONT. OGM detected significantly larger deletions and insertions than ONT (p-value -16 ). Regarding known movement disorder genes, a heterozygous intergenic deletion (195 kb) near ITPR1 was detected by both methods, and OGM validated a previously published 7 Mb inversion in PRKN . Heterozygous deletions in ATXN2 (1.4 kb), SUCLA2 (1.7 kb), and PNKD (2.6 kb) were detected by OGM and confirmed to be intronic by ONT. Conclusion: OGM allows for better detection of large insertions and can serve as a powerful first-line method to detect large pathogenic variants. However, it greatly benefits from a high-resolution sequencing technique like ONT to refine breakpoint positions. Despite certain limitations, ONT proved to be highly capable of detecting large variants independently; thus, it allows for a highly complementary assessment and validation of structural variation in combination with OGM.