Showing papers by "Kunikazu Tanji published in 2022"

Pathological substrate of memory impairment in multiple system atrophy

Abstract: Synaptic dysfunction in Parkinson's disease is caused by propagation of pathogenic α‐synuclein between neurons. Previously, in multiple system atrophy (MSA), pathologically characterised by ectopic deposition of abnormal α‐synuclein predominantly in oligodendrocytes, we demonstrated that the occurrence of memory impairment was associated with the number of α‐synuclein‐positive neuronal cytoplasmic inclusions (NCIs) in the hippocampus. In the present study, we aimed to investigate how abnormal α‐synuclein in the hippocampus can lead to memory impairment.

Accumulation of Nonfibrillar TDP-43 in the Rough Endoplasmic Reticulum Is the Early-Stage Pathology in Amyotrophic Lateral Sclerosis.

Abstract: Transactivation response DNA-binding protein 43 (TDP-43)-immunoreactive neuronal cytoplasmic inclusions (NCIs) are the histopathological hallmarks of amyotrophic lateral sclerosis (ALS). They are classified as skein-like inclusions, round inclusions, dot-like inclusions, linear wisps, and diffuse punctate cytoplasmic staining (DPCS). We hypothesized that TDP-43-immunoreactive DPCS may form the early-stage pathology of ALS. Hence, we investigated phosphorylated TDP-43 pathology in the upper and lower motor neurons of patients with ALS and control participants. We designated patients whose disease duration was ≤1 year as short-duration ALS (n = 7) and those whose duration equaled 3-5 years as standard-duration ALS (n = 6). DPCS and skein-like inclusions were the most common NCIs in short-duration and standard-duration ALS, respectively. The density of DPCS was significantly higher in short-duration ALS than that in standard-duration ALS and was inversely correlated with disease duration. DPCS was not ubiquitinated and disappeared after proteinase K treatment, suggesting that it was not aggregated. Immunoelectron microscopy revealed that DPCS corresponded to nonfibrillar TDP-43 localized to the ribosomes of the rough endoplasmic reticulum (ER). These findings suggest that nonfibrillar TDP-43 accumulation in the rough ER is the earliest TDP-43 pathology in ALS, which may be helpful in developing future TDP-43 breakdown strategies for ALS.

Sulforaphane Increase Mitochondrial Biogenesis-Related Gene Expression in the Hippocampus and Suppresses Age-Related Cognitive Decline in Mice

Abstract: Sulforaphane (SFN) is a potent activator of the transcriptional factor, Nuclear Factor Erythroid 2 (NF-E2)-Related factor 2 (NRF2). SFN and its precursor, glucoraphanin (sulforaphane glucosinolate, SGS), have been shown to ameliorate cognitive function in clinical trials and in vivo studies. However, the effects of SGS on age-related cognitive decline in Senescence-Accelerated Mouse Prone 8 (SAMP8) is unknown. In this study, we determined the preventive potential of SGS on age-related cognitive decline. One-month old SAMP8 mice or control SAM resistance 1 (SAMR1) mice were fed an ad libitum diet with or without SGS-containing broccoli sprout powder (0.3% w/w SGS in diet) until 13 months of age. SGS significantly improved long-term memory in SAMP8 at 12 months of age. Interestingly, SGS increased hippocampal mRNA and protein levels of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1α) and mitochondrial transcription factor A (TFAM), which are master regulators of mitochondrial biogenesis, both in SAMR1 and SAMP8 at 13 months of age. Furthermore, mRNAs for nuclear respiratory factor-1 (NRF-1) and mitochondrial DNA-encoded respiratory complex enzymes, but not mitochondrial DNA itself, were increased by SGS in SAMP8 mice. These results suggest that SGS prevents age-related cognitive decline by maintaining mitochondrial function in senescence-accelerated mice.

Praja1 RING‐finger E3 ubiquitin ligase is a common suppressor of neurodegenerative disease‐associated protein aggregation

Abstract: The formation of misfolded protein aggregates is one of the pathological hallmarks of neurodegenerative diseases. We have previously demonstrated the cytoplasmic aggregate formation of adenovirally expressed transactivation response DNA‐binding protein of 43 kDa (TDP‐43), the main constituent of neuronal cytoplasmic aggregates in cases of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), in cultured neuronal cells under the condition of proteasome inhibition. The TDP‐43 aggregate formation was markedly suppressed by co‐infection of adenoviruses expressing heat shock transcription factor 1 (HSF1), a master regulator of heat shock response, and Praja1 RING‐finger E3 ubiquitin ligase (PJA1) located downstream of the HSF1 pathway. In the present study, we examined other reportedly known E3 ubiquitin ligases for TDP‐43, i.e. Parkin, RNF112 and RNF220, but failed to find their suppressive effects on neuronal cytoplasmic TDP‐43 aggregate formation, although they all bind to TDP‐43 as verified by co‐immunoprecipitation. In contrast, PJA1 also binds to adenovirally expressed wild‐type and mutated fused in sarcoma, superoxide dismutase 1, α‐synuclein and ataxin‐3, and huntingtin polyglutamine proteins in neuronal cultures and suppressed the aggregate formation of these proteins. These results suggest that PJA1 is a common sensing factor for aggregate‐prone proteins to counteract their aggregation propensity, and could be a potential therapeutic target for neurodegenerative diseases that include ALS, FTLD, Parkinson's disease and polyglutamine diseases.

Inducible Systemic Gcn1 Deletion in Mice Leads to Transient Body Weight Loss upon Tamoxifen Treatment Associated with Decrease of Fat and Liver Glycogen Storage

Abstract: GCN1 is an evolutionarily-conserved ribosome-binding protein that mediates the amino acid starvation response as well as the ribotoxic stress response. We previously demonstrated that Gcn1 mutant mice lacking the GCN2-binding domain suffer from growth retardation and postnatal lethality via GCN2-independent mechanisms, while Gcn1-null mice die early in embryonic development. In this study, we explored the role of GCN1 in adult mice by generating tamoxifen-inducible conditional knockout (CKO) mice. Unexpectedly, the Gcn1 CKO mice showed body weight loss during tamoxifen treatment, which gradually recovered following its cessation. They also showed decreases in liver weight, hepatic glycogen and lipid contents, blood glucose and non-esterified fatty acids, and visceral white adipose tissue weight with no changes in food intake and viability. A decrease of serum VLDL suggested that hepatic lipid supply to the peripheral tissues was primarily impaired. Liver proteomic analysis revealed the downregulation of mitochondrial β-oxidation that accompanied increases of peroxisomal β-oxidation and aerobic glucose catabolism that maintain ATP levels. These findings show the involvement of GCN1 in hepatic lipid metabolism during tamoxifen treatment in adult mice.

Alteration of Vesicle-Associated Membrane Protein-Binding Protein B in α-Synuclein Aggregates in Lewy Body Disease.

Abstract: α-Synuclein (α-Syn) binds to vesicle-associated membrane protein-binding protein B (VAPB) in the endoplasmic reticulum membrane. Recent studies have shown that α-Syn-immunoreactive Lewy pathology is characterized by membrane crowding, including vesicular structures. To elucidate the role of VAPB and vesicular structures in Parkinson's disease (PD) and in dementia with Lewy bodies (DLB), the relationships among VAPB, vesicular structures, and Lewy pathology were investigated by immunohistochemistry and immunoelectron microscopy in 8 PD and 4 DLB autopsy cases. The proportions of VAPB-negative neurons in the substantia nigra in PD and in the temporal cortex in DLB were significantly higher than those in 5 controls. In PD, the incidence of α-Syn inclusions in VAPB-negative neurons was significantly higher (77.4%) than in VAPB-positive neurons (1.6%) in the substantia nigra. In DLB, the incidence of α-Syn inclusions in VAPB-negative neurons was also significantly higher (65.3%) than in VAPB-positive neurons (2.8%) in the temporal cortex. Immunoelectron microscopy revealed that α-Syn and VAPB were localized to filamentous structures of Lewy bodies (LBs). However, only a few vesicular structures labeled with anti-α-Syn were observed within LBs. These findings suggest that reduction of VAPB is involved in the disease processes of PD and DLB, although vesicular structures may not directly contribute to the formation of LBs.