Kazuki Muguruma, Tetsuya Takahashi, Yuichiro Tagane, Keyoumu Nazere, Naoyuki Hara, Masahiro Nakamori, Yu Yamazaki, Hiroyuki Morino and Hirofumi Maruyama : Intracellular anionic substances cause tau liquid-liquid phase separation., Biochemical and Biophysical Research Communications, Vol.757, 2025.
(Summary)
Tau protein aggregation plays an important role in the pathophysiology of neurodegenerative diseases, including Alzheimer's disease and Niemann-Pick disease type C. Liquid-liquid phase separation has emerged as a key mechanism in the early stages of protein aggregation for these disorders. Tau protein incubated with heparin undergoes liquid-liquid phase separation to form liquid droplets in vitro. However, whether tau liquid droplet formation occurs in vivo remains unresolved. To investigate cellular conditions that promote tau droplet formation, we treated tau-expressing human embryonic kidney 293T cells with reagents that introduced anionic substances or induced intracellular vesicle accumulation. Suppression of Niemann-Pick disease type C1 protein, a lysosomal membrane protein involved in mediating intracellular cholesterol trafficking, or the introduction of negatively charged dextran into cultured cells, increased the formation of tau-positive puncta with liquid droplet characteristics in a concentration-dependent manner. After prolonged observation, these puncta transitioned from a dynamic liquid state to a more solid-like gel phase, indicating progressive aggregation. Our findings suggest that intracellular enrichment of negatively charged substances or vesicles induces tau phase separation, potentially contributing to its pathological aggregation. These results provide insight into the molecular mechanisms underlying tauopathies and highlight potential targets for therapeutic intervention.
Kenta Hanada, Yusuke Osaki, Ryosuke Miyamoto, Kohei Muto, Shotaro Haji, Keyoumu Nazere, Yuki Kuwano, Hiroyuki Morino, Yoshiteru Azuma, Satoko Miyatake, Naomichi Matsumoto and Yuishin Izumi : Intermediate phenotype between CMT2Z and DIGFAN associated with a novel MORC2 variant: a case report., Human Genome Variation, Vol.11, No.1, 2024.
(Summary)
Charcot-Marie-Tooth disease type 2Z is caused by MORC2 mutations and presents with axonal neuropathy. MORC2 mutations can also manifest as developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (DIGFAN). We report a patient exhibiting an intermediate phenotype between these diseases associated with a novel MORC2 variant. A literature review revealed that the genotype‒phenotype correlation in MORC2-related disorders is complex and that the same mutation can cause a variety of phenotypes.
Takafumi Tomenaga, Shinobu Minatani, Hiroto Namba, Akitoshi Takeda, Takahito Yoshizaki, Joji Kawabe, Keyoumu Nazere, Hiroyuki Morino, Makoto Higuchi, Tomoyasu Matsubara, Hiroyuki Hatsuta, Masato Hasegawa, Shigeo Murayama and Yoshiaki Itoh : An autopsy case of type A FTLD-TDP with a GRN mutation presenting with the logopenic variant of primary progressive aphasia at onset and with corticobasal syndrome subsequently., Neuropathology, 2024.
(Summary)
A 68-year-old woman presented with difficulty finding words and writing characters. Neurological examination led to clinical diagnosis at onset of the logopenic variant of primary progressive aphasia accompanied with ideomotor apraxia, visuospatial agnosia on the right, and Gerstmann syndrome. Bradykinesia and rigidity on the right with shuffling gait developed after one year. Treatment with L-dopa had no effect. The patient was diagnosed with corticobasal syndrome (CBS). Brain magnetic resonance imaging revealed diffuse cortical atrophy dominantly on the left, especially in the temporal, parietal, and occipital lobes. Positron emission tomography did not reveal any significant accumulation of amyloid β or tau protein. She died five years later. Neuropathological examination revealed diffuse cortical atrophy with severe neuronal loss and fibrous gliosis in the cortex. Neuronal cytoplasmic inclusions, short dystrophic neurites, and, most notably, neuronal intranuclear inclusions, all immunoreactive for phosphorylated TDP-43, were observed. Western blotting revealed a full length and fragments of phosphorylated TDP-43 at 45 and 23kDa, respectively, confirming the pathological diagnosis of type A FTLD-TDP. Whole exome sequencing revealed a pathogenic mutation in GRN (c.87dupC). FTLD-TDP should be included in the differential diagnosis of CBS.
Keyoumu Nazere, Konoka Tachibana, Yuki Kuwano, Ryosuke Miyamoto, Ryuji Kaji, Yuishin Izumi and Hiroyuki Morino : The identification and functional analysis of novel variants in ADCY5- related movement disorders, 第65回日本神経学会学術大会/AOCN2024, May 2024.
3.
Yuki Kuwano, Keyoumu Nazere and Hiroyuki Morino : The biological role of m6A RNA methylation in cytoplasmic localization of TDP-43, 第65回日本神経学会学術大会/AOCN2024, May 2024.
YAMAUCHI Shoma, Ryosuke Miyamoto, MUTO Kohei, Yuki Kuwano, Keyoumu Nazere, Kensei Nishida, TACHIBANA Konoka, Yuishin Izumi and Hiroyuki Morino : Search for Pathogenic Variant of ALS by Prioritization based on Phenotype, 第64回日本神経学会学術大会, Jun. 2023.
Et cetera, Workshop:
1.
Yuki Kuwano, Keyoumu Nazere and Hiroyuki Morino : m6A RNAメチル化がトリガーするALS原因因子TDP-43の細胞質封入体形成の調節機構, 先端酵素学研究所交流シンポジウム, Aug. 2024.