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Mitochondrial dysfunction and lysosomal dysfunction have been implicated in Parkinson’s disease (PD), but the links between these dysfunctions in PD pathogenesis are still largely unknown. Here we report that cytosolic dsDNA of mitochondrial origin escaping from lysosomal degradation was shown to induce cytotoxicity in cultured cells and PD phenotypes in vivo. The depletion of PINK1, GBA and/or ATP13A2 causes increases in cytosolic dsDNA of mitochondrial origin and induces type I interferon (IFN) responses and cell death in cultured cell lines. These phenotypes are rescued by the overexpression of DNase II, a lysosomal DNase that degrades discarded mitochondrial DNA, or the depletion of IFI16, which acts as a sensor for cytosolic dsDNA of mitochondrial origin. Reducing the abundance of cytosolic dsDNA by overexpressing human DNase II ameliorates movement disorders and dopaminergic cell loss in gba mutant PD model zebrafish. Furthermore, IFI16 and cytosolic dsDNA puncta of mitochondrial origin accumulate in the brain of patients with PD. These results support a common causative role for the cytosolic leakage of mitochondrial DNA in PD pathogenesis. Mitochondrial and lysosomal dysfunction are central to Parkinson’s disease (PD) pathogenesis. Here, the authors show mitochondrial dsDNA in the cytosol in cellular and Zebrafish models of PD induces cytotoxicity and neurodegeneration; knock-down of IFI16, a cytosolic dsDNA sensor, rescues cytotoxicity, as does overexpression of lysosomal DNAse II.

Glia have been implicated in Alzheimer’s disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2 -dependent DAM and identified a previously undiscovered Serpina3n + C4b + reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2- R47H and TREM2 -R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences. Single-nucleus RNA sequencing in a mouse model of Aβ accumulation and postmortem brain tissue from people with Alzheimer’s disease reveals substantial species-specific differences in transcriptional signatures, but both point to the contribution of glia and the importance of TREM2.

Whole-organ/body three-dimensional (3D) staining and imaging have been enduring challenges in histology. By dissecting the complex physicochemical environment of the staining system, we developed a highly optimized 3D staining imaging pipeline based on CUBIC. Based on our precise characterization of biological tissues as an electrolyte gel, we experimentally evaluated broad 3D staining conditions by using an artificial tissue-mimicking material. The combination of optimized conditions allows a bottom-up design of a superior 3D staining protocol that can uniformly label whole adult mouse brains, an adult marmoset brain hemisphere, an ~1 cm 3 tissue block of a postmortem adult human cerebellum, and an entire infant marmoset body with dozens of antibodies and cell-impermeant nuclear stains. The whole-organ 3D images collected by light-sheet microscopy are used for computational analyses and whole-organ comparison analysis between species. This pipeline, named CUBIC-HistoVIsion, thus offers advanced opportunities for organ- and organism-scale histological analysis of multicellular systems. Tissue clearing has revolutionised histology, but limited penetration of antibodies and stains into thick tissue segments is still a bottleneck. Here, the authors characterise optically cleared tissue as an electrolyte gel and apply this knowledge to stain the entirety of thick tissue samples.

The TREM2–DAP12 receptor complex sustains microglia functions. Heterozygous hypofunctional TREM2 variants impair microglia, accelerating late-onset Alzheimer’s disease. Homozygous inactivating variants of TREM2 or TYROBP- encoding DAP12 cause Nasu–Hakola disease (NHD), an early-onset dementia characterized by cerebral atrophy, myelin loss and gliosis. Mechanisms underpinning NHD are unknown. Here, single-nucleus RNA-sequencing analysis of brain specimens from DAP12-deficient NHD individuals revealed a unique microglia signature indicating heightened RUNX1, STAT3 and transforming growth factor-β signaling pathways that mediate repair responses to injuries. This profile correlated with a wound healing signature in astrocytes and impaired myelination in oligodendrocytes, while pericyte profiles indicated vascular abnormalities. Conversely, single-nuclei signatures in mice lacking DAP12 signaling reflected very mild microglial defects that did not recapitulate NHD. We envision that DAP12 signaling in microglia attenuates wound healing pathways that, if left unchecked, interfere with microglial physiological functions, causing pathology in human. The identification of a dysregulated NHD microglia signature sparks potential therapeutic strategies aimed at resetting microglia signaling pathways. Colonna and colleagues report dysregulated gene expression in microglia harboring homozygous mutations of DAP12 from individuals with Nasu–Hakola disease, a form of early-onset dementia.

ABSTRACTSenile plaques (SPs) containing amyloid β peptide (Aβ) 1–42 are the major species present in Alzheimer disease (AD), whereas Aβ1–40 is the major constituent of arteriolar walls affected by cerebral amyloid angiopathy. The water channel proteins astrocytic aquaporin 1 (AQP1) and aquaporin 4 (AQP4) are known to be abnormally expressed in AD brains, but the expression of AQPs surrounding SPs and cerebral amyloid angiopathy has not been described in detail. Here, we investigated whether AQP expression is associated with each species of Aβ deposited in human brains affected by either sporadic or familial AD. Immunohistochemical analysis demonstrated more numerous AQP1-positive reactive astrocytes in the AD cerebral cortex than in controls, located close to Aβ42- or Aβ40-positive SPs. In AD cases, however, AQP1-positive astrocytes were not often observed in Aβ-rich areas, and there was a significant negative correlation between the levels of AQP1 and Aβ42 assessed semiquantitatively. We also found that Aβ plaque-like AQP4 was distributed in association with Aβ42- or Aβ40-positive SPs and that the degree of AQP4 expression around Aβ40-positive vessels was variable. These findings suggest that a defined population of AQP1-positive reactive astrocytes may modify Aβ deposition in the AD brain, whereas the Aβ deposition process might alter astrocytic expression of AQP4.

Tauopathies are the most common type of neurodegenerative proteinopathy, being characterized by cytoplasmic aggregates of hyperphosphorylated tau protein. The formation and morphologies of these tau inclusions, the distribution of the lesions and related metabolic changes in cytoplasm differ among different tauopathies. The aim of this study was to examine whether there are differences in the post-translational modifications (PTMs) in the pathological tau proteins. We analyzed sarkosyl-insoluble pathological tau proteins prepared from brains of patients with Alzheimer's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, globular glial tauopathy, and frontotemporal dementia and parkinsonisms linked to chromosome 17 with tau inclusions using liquid chromatography mass spectrometry. In pathological tau proteins associated with a wide range of tauopathies, 170 PTMs in total were identified including new PTMs. Among them, common PTMs were localized in the N- and C-terminal flanking regions of the microtubule binding repeats and PTMs, which were considered to be disease-specific, were found in microtubule binding repeats forming filament core. These suggested that the differences in PTMs reflected the differences in tau filament core structures in each disease.

White matter injury is caused by cerebral blood flow disturbances associated with stroke and demyelinating diseases such as multiple sclerosis. Remyelination is induced spontaneously after white matter injury, but progressive multiple sclerosis and white matter stroke are usually characterised by remyelination failure. However, the mechanisms underlying impaired remyelination in lesions caused by demyelination and stroke remain unclear. In the current study, we demonstrated that collagen fibres accumulated in the demyelinated lesions of multiple sclerosis patients (age range 23–80 years) and white matter lesions of stroke patients (age range 80–87 years), suggesting that the accumulation of collagen fibres correlates with remyelination failure in these lesions. To investigate the function of collagen fibres in the white matter lesions, we generated two types of white matter injury in mice. We induced focal demyelination by lysolecithin (LPC) injection and ischemic stroke by endothelin 1 (ET1) injection into the internal capsule. We found that type I collagen fibres were secreted in ET1-induced lesions with impaired white matter regeneration in the chronic phase of disease. We also showed that monocyte-derived macrophages that infiltrated into lesions from the peripheral blood produced type I collagen after white matter injury, and that type I collagen also exacerbated microglial activation, astrogliosis, and axonal injury. Finally, we demonstrated that oligodendrocyte differentiation and remyelination were inhibited in the presence of type I collagen after LPC-induced demyelination. These results suggest that type I collagen secreted by monocyte-derived macrophages inhibited white matter regeneration, and therefore, the modulation of type I collagen metabolism might be a novel therapeutic target for white matter injury.

The aberrant accumulation of ubiquitinated protein aggregates in cells plays a critical role in the pathogenesis of several degenerative diseases, including Parkinson disease (PD) and cystic fibrosis (CF). In this study, we found that Ras GTPase-activating protein-binding protein 1 (G3BP1) inhibits ubiquitinated protein aggregations induced by p62 and USP10 in cultured cells. p62 is a ubiquitin receptor, and p62 and its binding partner USP10 have been shown to augment ubiquitinated protein aggregation. G3BP1 interacted with p62 and USP10 and inhibited p62/USP10-induced protein aggregation. The G3BP1 inhibition of protein aggregations targeted two aggregation-prone proteins, α-synuclein and CFTR-ΔF508, which are causative factors of PD and CF, respectively. G3BP1 depletion increased the amounts of ubiquitinated α-synuclein and CFTR-ΔF508 protein. A proteasome reporter indicated that G3BP1 depletion inhibits the proteasome activity. We herein present evidence that G3BP1, p62 and USP10 together control ubiquitinated protein toxicity by controlling both ubiquitination and aggregation. Taken together, these results suggest that G3BP1, p62 and USP10 could be therapeutic targets for ubiquitinated protein aggregation disorders, including PD and CF.

Tau aggregates in neurons of brain lesions is a hallmark pathology of tauopathies, including Alzheimer’s disease (AD). Recent studies suggest that the RNA-binding protein TIA1 initiates Tau aggregation by inducing the formation of stress granules (SGs) containing Tau. SGs are stress-inducible cytoplasmic protein aggregates containing many RNA-binding proteins that has been implicated as an initial site of multiple pathogenic protein aggregates in several neurodegenerative diseases. In this study, we found that ubiquitin-specific protease 10 (USP10) is a critical factor for the formation of Tau/TIA1/USP10-positive SGs. Proteasome inhibition or TIA1-overexpression in HT22 neuronal cells induced the formation of TIA1/Tau-positive SGs, and the formations were severely attenuated by depletion of USP10. In addition, the overexpression of USP10 without stress stimuli in HT22 cells induced TIA1/Tau/USP10-positive SGs in a deubiquitinase-independent manner. In AD brain lesions, USP10 was colocalized with Tau aggregates in the cell body of neurons. The present findings suggest that USP10 plays a key role in the initiation of pathogenic Tau aggregation in AD through SG formation.

The figure shows tissue samples taken from three previous cases, revealing the cause of hemosiderin deposition in the central nervous system because of superficial siderosis.The figure shows tissue samples taken from three previous cases, revealing the cause of hemosiderin deposition in the central nervous system because of superficial siderosis.