Explore the vast range of titles available.

Study objectives To describe a case series of patients with prominent sleep disturbances and their polysomnography findings in six patients with dipeptidyl-peptidase-like protein-6 (DPPX) autoimmunity syndrome. Methods Of 13 patients with DPPX autoimmunity evaluated at Mayo Clinic, 6 were seen by Sleep Medicine with polysomnography and were assessed with blood and cerebrospinal fluid, neuroimaging, neuropsychological testing, and evaluation tailored to clinical presentation. Results Median age of our six DPPX autoimmunity patients was 57 (range 27–70) years, with one woman. All patients had prominent gastrointestinal disturbances, most with prominent and early weight loss, and a spectrum of neuropsychiatric disturbances including cognitive impairment, myoclonus, exaggerated startle, and dysautonomia. Sleep disturbances included insomnia and obstructive sleep apnea in six patients, periodic leg movements of sleep in four, and REM sleep behavior disorder in two. Polysomnography demonstrated REM sleep-atonia loss in four patients, and ambiguous sleep with status dissociatus (mixed features of wakefulness, non-rapid eye movement [NREM], and REM sleep) appeared in one patient. Five of six patients showed neurological improvement with immunotherapy, including three with at least partial improvement in sleep disturbances. Conclusion Our patients with DPPX autoimmunity syndrome had prominent sleep disturbances including sleep-disordered breathing, REM sleep behavior disorder, and abnormal NREM sleep architecture with highly variable clinical presentations. DPPX autoimmunity should be considered in cases with a triad of sleep disturbance, neurological features of hyperexcitability, and systemic symptoms of gastrointestinal disturbance and weight loss. Future prospective studies of DPPX autoimmunity syndrome including detailed sleep evaluation and follow-up are necessary.

Values for normative REM sleep without atonia (RSWA) remain unclear. Older age and male sex are associated with greater RSWA, and isolated elevated RSWA has been reported. We aimed to describe normative RSWA and characterize isolated RSWA frequency in adults without REM sleep behavior disorder (RBD). We visually quantified phasic, \"any,\" and tonic RSWA in the submentalis (SM) and anterior tibialis (AT) muscles, and the automated Ferri REM Atonia Index during polysomnography in adults without RBD aged 21-88. We calculated RSWA percentiles across age and sex deciles and compared RSWA in older (≥ 65) versus younger (<65) men and women. Isolated RSWA (exceeding diagnostic RBD cutoffs, or >95th percentile) frequency was also determined. Overall, 95th percentile RSWA percentages were SM phasic, any, tonic = 8.6%, 9.1%, 0.99%; AT phasic and \"any\" = 17.0%; combined SM/AT phasic, \"any\" = 22.3%, 25.5%; and RAI = 0.85. Most phasic RSWA burst durations were ≤1.0 s (85th percentiles: SM = 1.07, AT = 0.86 seconds). Older men had significantly higher AT RSWA than older women and younger patients (all p < 0.04). Twenty-nine (25%, 18 men) had RSWA exceeding the cohort 95th percentile, while 17 (14%, 12 men) fulfilled diagnostic cutoffs for phasic or automated RBD RSWA thresholds. RSWA levels are highest in older men, mirroring the demographic characteristics of RBD, suggesting that older men frequently have altered REM sleep atonia control. These data establish normative adult RSWA values and thresholds for determination of isolated RSWA elevation, potentially aiding RBD diagnosis and discussions concerning incidental RSWA in clinical sleep medicine practice.

Microglia play important roles in brain development and homeostasis by removing dying neurons through efferocytosis. Morphological changes in microglia are hallmarks of many neurodegenerative conditions, such as Niemann-Pick disease type C. Here, NPC1 loss causes microglia to shift from a branched to an ameboid form, though the cellular basis and functional impact of this change remain unclear. Using zebrafish, we show that NPC1 deficiency causes an efferocytosis-dependent expansion of the microglial gastrosome, a collection point for engulfed material. In vivo and in vitro experiments on microglia and mammalian macrophages demonstrate that NPC1 localizes to the gastrosome, and its absence leads to cholesterol accumulation in this compartment. NPC1 loss and neuronal cell death synergistically affect gastrosome size and cell shape, increasing the sensitivity of NPC1-deficient cells to neuronal cell death. Finally, we demonstrate conservation of cholesterol accumulation and gastrosome expansion in NPC patient-derived fibroblasts, offering an interesting target for further disease investigation. In Niemann-Pick type C, microglia display an ameboid shape. Here, the authors show that this is tied to neuronal engulfment and the expansion of the gastrosome, where cholesterol accumulates, making microglia more sensitive to neuronal cell death levels.

Key Points A mutation in the protein huntingtin causes the devastating neurodegenerative disorder Huntington's disease (HD). Huntingtin is a high-molecular-weight, ubiquitously expressed protein that has no sequence homology with other proteins and a fundamental role in embryonic development. It seems to have appeared some millions of years ago, before the divergence of the protostoma (which gave rise to insects) and deuterostoma (mammals) branches. Biological evidence shows that huntingtin is anti-apoptotic in vitro and in vivo . This cell-autonomous activity can be shown in neuronal and non-neuronal cells, and is contained in the 548 amino acid terminus (N548) of the protein. In addition, huntingtin protects neurons from excitotoxicity in vivo . In the search for additional functions of wild-type huntingtin that could be more neuron-specific, huntingtin was found to stimulate brain-derived neurotrophic factor ( BDNF ) gene transcription through inhibition of a silencer element (Repressor element 1, also known as neuron-restrictive silencer element, NRSE) located in the promoter of the BDNF gene. Through a similar mechanism, huntingtin controls the transcription of many other neuronal genes that carry an RE1/NRSE in their promoters. Wild-type huntingtin also regulates fast axonal trafficking, vesicle transport (including transport of BDNF) and synaptic transmission, and so has a crucial role in normal brain function. Mutation of huntingtin causes reduced BDNF production, enhanced activity of the RE1/NRSE silencer (with repression of neuronal gene transcription), reduced transport of mitochondria and BDNF, altered synaptic transmission and many other alterations as a consequence of its increased toxicity. Whereas increased expression of wild-type huntingtin leads to increased survival and BDNF production, its depletion produces some (but not all) of the phenotypes observed in HD mice. This suggests that reduced huntingtin activity might have a role in HD and that wild-type huntingtin might act as a modifier of HD pathology. Wild-type huntingtin levels have been manipulated by its overexpression or depletion in HD models. Its overexpression reduces mutant huntingtin toxicity in HD cells in vitro and in the testes of HD transgenic mice. Its reduced level in HD mice causes a worsening of some of the HD phenotypes. Finally, reducing the level of BDNF in HD mice causes earlier onset of symptoms and increased motor dysfunction. Huntingtin is, therefore, endowed with important functions in the healthy brain. Some of these same functions are reduced in HD, so wild-type huntingtin might act as a modifier of HD pathology. Restoring the activity of its downstream targets could be beneficial to patients with this disorder. Several neurological diseases are characterized by the altered activity of one or a few ubiquitously expressed cell proteins, but it is not known how these normal proteins turn into harmful executors of selective neuronal cell death. We selected huntingtin in Huntington's disease to explore this question because the dominant inheritance pattern of the disease seems to exclude the possibility that the wild-type protein has a role in the natural history of this condition. However, even in this extreme case, there is considerable evidence that normal huntingtin is important for neuronal function and that the activity of some of its downstream effectors, such as brain-derived neurotrophic factor, is reduced in Huntington's disease.

In this study, the authors show that cell-autonomous expression of mutant Huntingtin in microglia can elicit alterations in the transcriptional profile and activation state of the cells. In particular, there is an upregulation of pro-inflammatory and myeloid lineage factors and an increased ability to promote neuronal death after inflammatory insult. Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an extended polyglutamine repeat in the N terminus of the Huntingtin protein (HTT). Reactive microglia and elevated cytokine levels are observed in the brains of HD patients, but the extent to which neuroinflammation results from extrinsic or cell-autonomous mechanisms in microglia is unknown. Using genome-wide approaches, we found that expression of mutant Huntingtin (mHTT) in microglia promoted cell-autonomous pro-inflammatory transcriptional activation by increasing the expression and transcriptional activities of the myeloid lineage-determining factors PU.1 and C/EBPs. We observed elevated levels of PU.1 and its target genes in the brains of mouse models and individuals with HD. Moreover, mHTT-expressing microglia exhibited an increased capacity to induce neuronal death ex vivo and in vivo in the presence of sterile inflammation. These findings suggest a cell-autonomous basis for enhanced microglia reactivity that may influence non-cell-autonomous HD pathogenesis.

Human telencephalon is an evolutionarily advanced brain structure associated with many uniquely human behaviors and disorders. However, cell lineages and molecular pathways implicated in human telencephalic development remain largely unknown. We produce human telencephalic organoids from stem cell-derived single neural rosettes and investigate telencephalic development under normal and pathological conditions. We show that single neural rosette-derived organoids contain pallial and subpallial neural progenitors, excitatory and inhibitory neurons, as well as macroglial and periendothelial cells, and exhibit predictable organization and cytoarchitecture. We comprehensively characterize the properties of neurons in SNR-derived organoids and identify transcriptional programs associated with the specification of excitatory and inhibitory neural lineages from a common pool of NPs early in telencephalic development. We also demonstrate that neurons in organoids with a hemizygous deletion of an autism- and intellectual disability-associated gene SHANK3 exhibit intrinsic and excitatory synaptic deficits and impaired expression of several clustered protocadherins. Collectively, this study validates SNR-derived organoids as a reliable model for studying human telencephalic cortico-striatal development and identifies intrinsic, synaptic, and clustered protocadherin expression deficits in human telencephalic tissue with SHANK3 hemizygosity. Our understanding of human brain development in health and disease is limited. The authors generated human brain organoids from stem cell-derived isolated single neural rosettes to study human cortico-striatal development and deficits caused by an autism-associated genetic abnormality in SHANK3.

Lysosomes are organelles central to degradation and recycling processes in animal cells. Whether lysosomal activity is coordinated to respond to cellular needs remains unclear. We found that most lysosomal genes exhibit coordinated transcriptional behavior and are regulated by the transcription factor EB (TFEB). Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes. TFEB overexpression in cultured cells induced lysosomal biogenesis and increased the degradation of complex molecules, such as glycosaminoglycans and the pathogenic protein that causes Huntington's disease. Thus, a genetic program controls lysosomal biogenesis and function, providing a potential therapeutic target to enhance cellular clearing in lysosomal storage disorders and neurodegenerative diseases.

Huntington’s disease (HD) causes selective degeneration of striatal and cortical neurons, resulting in cell mosaicism of coexisting still functional and dysfunctional cells. The impact of non-cell autonomous mechanisms between these cellular states is poorly understood. Here we generated telencephalic organoids with healthy or HD cells, grown separately or as mosaics of the two genotypes. Single-cell RNA sequencing revealed neurodevelopmental abnormalities in the ventral fate acquisition of HD organoids, confirmed by cytoarchitectural and transcriptional defects leading to fewer GABAergic neurons, while dorsal populations showed milder phenotypes mainly in maturation trajectory. Healthy cells in mosaic organoids restored HD cell identity, trajectories, synaptic density, and communication pathways upon cell-cell contact, while showing no significant alterations when grown with HD cells. These findings highlight cell-type-specific alterations in HD and beneficial non-cell autonomous effects of healthy cells, emphasizing the therapeutic potential of modulating cell-cell communication in disease progression and treatment. Mosaic organoids where pathological and healthy cells are grown together, reveal the rescue of phenotypes in pathological cells due to communication with healthy cells without harming them, as demonstrated by single-cell RNA-sequencing data.

Spectral Counts approaches (SpCs) are largely employed for the comparison of protein expression profiles in label-free (LF) differential proteomics applications. Similarly, to other comparative methods, also SpCs based approaches require a normalization procedure before Fold Changes (FC) calculation. Here, we propose new Complexity Based Normalization (CBN) methods that introduced a variable adjustment factor (f), related to the complexity of the sample, both in terms of total number of identified proteins (CBN(P)) and as total number of spectral counts (CBN(S)). Both these new methods were compared with the Normalized Spectral Abundance Factor (NSAF) and the Spectral Counts log Ratio (Rsc), by using standard protein mixtures. Finally, to test the robustness and the effectiveness of the CBNs methods, they were employed for the comparative analysis of cortical protein extract from zQ175 mouse brains, model of Huntington Disease (HD), and control animals (raw data available via ProteomeXchange with identifier PXD017471). LF data were also validated by western blot and MRM based experiments. On standard mixtures, both CBN methods showed an excellent behavior in terms of reproducibility and coefficients of variation (CVs) in comparison to the other SpCs approaches. Overall, the CBN(P) method was demonstrated to be the most reliable and sensitive in detecting small differences in protein amounts when applied to biological samples.

A disintegrine and metalloproteinase 10 (ADAM10) is implicated in synaptic function through its interaction with postsynaptic receptors and adhesion molecules. Here, we report that levels of active ADAM10 are increased in Huntington's disease (HD) mouse cortices and striata and in human postmortem caudate. We show that, in the presence of polyglutamine-expanded (polyQ-expanded) huntingtin (HTT), ADAM10 accumulates at the postsynaptic densities (PSDs) and causes excessive cleavage of the synaptic protein N-cadherin (N-CAD). This aberrant phenotype is also detected in neurons from HD patients where it can be reverted by selective silencing of mutant HTT. Consistently, ex vivo delivery of an ADAM10 synthetic inhibitor reduces N-CAD proteolysis and corrects electrophysiological alterations in striatal medium-sized spiny neurons (MSNs) of 2 HD mouse models. Moreover, we show that heterozygous conditional deletion of ADAM10 or delivery of a competitive TAT-Pro-ADAM10709-729 peptide in R6/2 mice prevents N-CAD proteolysis and ameliorates cognitive deficits in the mice. Reduction in synapse loss was also found in R6/2 mice conditionally deleted for ADAM10. Taken together, these results point to a detrimental role of hyperactive ADAM10 at the HD synapse and provide preclinical evidence of the therapeutic potential of ADAM10 inhibition in HD.