When proteostasis becomes unbalanced, unfolded proteins can accumulate and aggregate. Here we report that the dye, tetraphenylethene maleimide (TPE-MI) can be used to measure cellular unfolded protein load. TPE-MI fluorescence is activated upon labelling free cysteine thiols, normally buried in the core of globular proteins that are exposed upon unfolding. Crucially TPE-MI does not become fluorescent when conjugated to soluble glutathione. We find that TPE-MI fluorescence is enhanced upon reaction with cellular proteomes under conditions promoting accumulation of unfolded proteins. TPE-MI reactivity can be used to track which proteins expose more cysteine residues under stress through proteomic analysis. We show that TPE-MI can report imbalances in proteostasis in induced pluripotent stem cell models of Huntington disease, as well as cells transfected with mutant Huntington exon 1 before the formation of visible aggregates. TPE-MI also detects protein damage following dihydroartemisinin treatment of the malaria parasites Plasmodium falciparum. TPE-MI therefore holds promise as a tool to probe proteostasis mechanisms in disease.

Competing models exist in the literature for the relationship between mutant Huntingtin exon 1 (Httex1) inclusion formation and toxicity. In one, inclusions are adaptive by sequestering the proteotoxicity of soluble Httex1. In the other, inclusions compromise cellular activity as a result of proteome co-aggregation. Using a biosensor of Httex1 conformation in mammalian cell models, we discovered a mechanism that reconciles these competing models. Newly formed inclusions were composed of disordered Httex1 and ribonucleoproteins. As inclusions matured, Httex1 reconfigured into amyloid, and other glutamine-rich and prion domain-containing proteins were recruited. Soluble Httex1 caused a hyperpolarized mitochondrial membrane potential, increased reactive oxygen species, and promoted apoptosis. Inclusion formation triggered a collapsed mitochondrial potential, cellular quiescence, and deactivated apoptosis. We propose a revised model where sequestration of soluble Httex1 inclusions can remove the trigger for apoptosis but also co-aggregate other proteins, which curtails cellular metabolism and leads to a slow death by necrosis.

Early cell death is a feature of neurodegenerative disorders. Telomere shortening is related to premature cellular senescence and could be a marker for cellular pathology in neurological diseases. Relative telomere length in dementia (N=70), Huntington's disease (N=35), ataxia telangiectasia (N=9), and age-group matched control samples (N=105) was measured as relative telomere copy/single copy gene ratios. Individuals with Huntington's disease had the lowest relative telomere copy/single copy gene ratio (0.21), followed by ataxia telangiectasia (0.31) and dementia (0.48). The younger control group had the highest relative telomere copy/single copy gene ratio (1.07). The reduced telomere length could be indicative of shared biological pathways across these disorders contributing to cellular senescence.

Marginal zone (MZ) B cells produce broad-spectrum antibodies that protect against infection early in life. In some instances, antibody production requires MZ B cells to display pathogen antigens bound to major histocompatibility complex class II (MHC II) molecules to T cells. We describe the trogocytic acquisition of these molecules from conventional dendritic cells (cDCs). Complement component 3 (C3) binds to murine and human MHC II on cDCs. MZ B cells recognize C3 with complement receptor 2 (CR2) and trogocytose the MHC II–C3 complexes, which become exposed on their cell surface. The ubiquitin ligase MARCH1 limits the number of MHC II–C3 complexes displayed on cDCs to prevent their elimination through excessive trogocytosis. Capture of C3 by MHC II thus enables the transfer of cDC-like properties to MZ B cells.

Aim:Telomere attrition has been noted in many neuropsychiatric and neurodegenerative syndromes, and may indicate a shared molecular pathology across conditions. We evaluated telomere length in subjects with remitted and unremitted schizophrenia and in control subjects. Methods:We measured telomere length as relative telomere/single-copy gene ratios in subjects with schizophrenia (n = 71) using quantitative real-time polymerase chain reaction. This was compared with relative telomere/single-copy gene ratios in agematched controls without neuropsychiatric illness (n = 73). Results:The relative telomere/single-copy gene ratios were significantly lower in subjects with unremitted schizophrenia when compared with control subjects (r = −0.281, P = 0.003), as well as the individuals with remitted schizophrenia. Conclusion:The lower relative telomere length in unremitted schizophrenia subjects may thus indicate shared biological pathways with other neurodegenerative disorders that are also characterized by increased cellular senescence.

Huntington's disease is caused by polyglutamine (polyQ)-expansion mutations in the CAG tandem repeat of the Huntingtin gene. The central feature of Huntington's disease pathology is the aggregation of mutant Huntingtin (Htt) protein into micrometer-sized inclusion bodies. Soluble mutant Htt states are most proteotoxic and trigger an enhanced risk of death whereas inclusions confer different changes to cellular health, and may even provide adaptive responses to stress. Yet the molecular mechanisms underpinning these changes remain unclear. Using the flow cytometry method of pulse-shape analysis (PulSA) to sort neuroblastoma (Neuro2a) cells enriched with mutant or wild-type Htt into different aggregation states, we clarified which transcriptional signatures were specifically attributable to cells before versus after inclusion assembly. Dampened CREB signalling was the most striking change overall and invoked specifically by soluble mutant Httex1 states. Toxicity could be rescued by stimulation of CREB signalling. Other biological processes mapped to different changes before and after aggregation included NF-kB signalling, autophagy, SUMOylation, transcription regulation by histone deacetylases and BRD4, NAD+ biosynthesis, ribosome biogenesis and altered HIF-1 signalling. These findings open the path for therapeutic strategies targeting key molecular changes invoked prior to, and subsequently to, Httex1 aggregation.

Huntington's disease is characterized by choreic movements, psychiatric disorders, striatal atrophy with selective small neuronal loss, and autosomal dominant inheritance. The genetic abnormality is CAG expansion in Huntingtin gene. Newer therapeutic strategies are evolving to treat this progressive disorder. The neuroprotective agents are one such group of drugs being tried. Lithium has been used to treat Huntington's disease in the past due to its neuroprotective effects. Though the precise mechanism of action is not clear, Lithium can directly or indirectly modulate proteins involved in neuronal survival/differentiation which may account for its neuroprotective effects. We report three patients with Huntington's disease in whom Lithium prevented the progression of chorea and also helped stabilize mood.

Huntington's disease (HD), an autosomal dominant neurodegenerative syndrome, has a world-wide distribution. An estimated 2.5-10/100,000 people of European ancestry are affected with HD, while the Asian populations have lower prevalence (0.6-3.8/100,000). The epidemiology of HD is not well described in India, and the distribution of the pathogenic CAG expansion, and the associated haplotype, in this population needs to be better understood. This study demonstrates a distribution of CAG repeats, at the HTT locus, comparable to the European population in both normal and HD affected chromosomes. Further, we provide an evidence for similarity of the HD halpotype in Indian sample to the European HD haplogroup. Funding StatementThis study is supported by Indian Council of Medical Research (ICMR/002/208/2012/00126). The sponsor of this study had no role in study design, data collection, analysis, interpretation, or writing of the report. No private corporations or other agency paid to write this article. All the authors had full access to all the data in the study. All authors have seen and given their approval for submission of the manuscript. All the authors declare no conflict of interest in study undertaken. IntroductionThe diagnosis of Huntington's disease (HD) is based on estimation of the CAG repeat length at the HTT locus 1 . The normal HTT gene contains less than 27 CAG repeats 2 , 3 , and a few normal individuals have intermediate CAG (27)(28)(29)(30)(31)(32)(33)(34)(35) repeat expansion 2 and display no symptoms suggestive of HD. Subjects with borderline CAG (36)(37)(38)(39) repeats may or may not develop symptoms. Individuals affected with HD typically have at least one HTT allele containing CAG repeat size of 40 or greater 2 , 4 .The age at onset (AAO) is inversely correlated with length of the pathogenic CAG stretch in the HTT gene 5 . Almost 50-70% of the variation observed is determined by the CAG repeat length, the remaining maybe explained by the additional influence of other cis and trans elements, as well as environmental factors 5 . Highly expanded CAG sequences cause disease onset at a younger age 6 . The fundamental mechanisms of CAG repeat instability are poorly understood.The prevalence of HD varies among different populations, with prevalence rates of 2.5 -10 per 100,000 in people of European ancestry, while the Japanese (0.11-0.45 per 100,000), Chinese ( 0.5-1 per 100,000) and African populations (<0.01 per 100, 000) show significantly lower prevalence 7 . Indian and other South Asian populations are expected to have intermediate prevalence of HD. Prevalence studies of Indian immigrants in UK, predominantly from the northern regions of the Indian subcontinent 8 suggest that HD occurs in 1.75 per 100,000 individuals. It is generally accepted from clinical experience, and family studies of different geographical regions, that HD is distributed widely in India 9 , 10 , 11 , 12 . The origin of the pathogenic CAG expansion in India is not well understood. Multiple founder effects, and admix...