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Mutations in SNCA, the gene encoding α-synuclein (αSyn), cause familial Parkinson’s disease (PD) and aberrant αSyn is a key pathological hallmark of idiopathic PD. This α-synucleinopathy leads to mitochondrial dysfunction, which may drive dopaminergic neurodegeneration. PARKIN and PINK1, mutated in autosomal recessive PD, regulate the preferential autophagic clearance of dysfunctional mitochondria (“mitophagy”) by inducing ubiquitylation of mitochondrial proteins, a process counteracted by deubiquitylation via USP30. Here we show that loss of USP30 in Usp30 knockout mice protects against behavioral deficits and leads to increased mitophagy, decreased phospho-S129 αSyn, and attenuation of SN dopaminergic neuronal loss induced by αSyn. These observations were recapitulated with a potent, selective, brain-penetrant USP30 inhibitor, MTX115325, with good drug-like properties. These data strongly support further study of USP30 inhibition as a potential disease-modifying therapy for PD. USP30 has been proposed to regulate mitophagy, a relevant Parkinson’s disease mechanism. Here, the authors show that Usp30 knockout mice and USP30 inhibitors like MTX115325 demonstrate neuroprotective responses in an alpha-synuclein mouse model of Parkinson’s disease.

The receptor tyrosine kinase product of the anaplastic lymphoma kinase (ALK) gene has been implicated in oncogenesis as a product of several chromosomal translocations, although its endogeneous role in the hematopoietic and neural systems has remained poorly understood. We describe that the generation of animals homozygous for a deletion of the ALK tyrosine kinase domain leads to alterations in adult brain function. Evaluation of adult ALK homozygotes (HOs) revealed an age-dependent increase in basal hippocampal progenitor proliferation and alterations in behavioral tests consistent with a role for this receptor in the adult brain. ALK HO animals displayed an increased struggle time in the tail suspension test and the Porsolt swim test and enhanced performance in a novel object-recognition test. Neurochemical analysis demonstrates an increase in basal dopaminergic signalling selectively within the frontal cortex. Altogether, these results suggest that ALK functions in the adult brain to regulate the function of the frontal cortex and hippocampus and identifies ALK as a new target for psychiatric indications, such as schizophrenia and depression, with an underlying deregulated monoaminergic signalling.

Aberrant activation of the WNT/CTNNB1 pathway is notorious in colorectal cancer (CRC). Here, we demonstrate that the expression of specific and crucial WNT signaling pathway genes is linked to disease progression in colonic adenomatous (AP) and hyperplastic (HP) polyps in an Iranian patient population. Thus, we highlight potential gene expression profiles as candidate novel biomarkers for the early detection of CRC. From a 12-month study (2016-2017), 44 biopsy samples were collected during colonoscopy from the patients with colorectal polyps and 10 healthy subjects for normalization. Clinical and demographic data were collected in all cases, and mRNA expression of APC, CTNNB1, CDH1, AXIN1, and AXIN2 genes was investigated using real-time polymerase chain reaction (PCR). CTNNB1 and CDH1 expression levels were unaltered in AP and HP subjects, whereas mRNA expression of APC was decreased in AP contrasted with HP subjects, with a significant association between APC downregulation and polyp size. Although AXIN1 showed no changes between AP and HP groups, a significant association between AXIN1 and dysplasia grade was found. Also, significant upregulation of AXIN2 in both AP and HP subjects was detected. In summary, we have shown increased expression of AXIN2 and decreased expression of APC correlating with grade of dysplasia and polyp size. Hence, AXIN2 and APC should be explored as biomarker candidates for early detection of AP and HP polyps in CRC.

The aganglionic bowel in short‐segment Hirschsprung's disease is characterized both by the absence of enteric ganglia and the presence of extrinsic thickened nerve bundles (TNBs). The relationship between the TNBs and the loss of enteric ganglia is unknown. Previous studies have described decreasing numbers of ganglia with increasing density of TNBs within the transition zone (TZ) between ganglionic and aganglionic gut, and there is some evidence of spatial contact between them in this region. To determine the cellular interactions involved, we have analysed the expression of perineurial markers of TNBs and enteric ganglionic markers for both neural cells and their ensheathing telocytes across four cranio‐caudal segments consisting of most proximal ganglionic to most distal aganglionic from pull‐through resected colon. We show that in the TZ, enteric ganglia are abnormal, being surrounded by perineurium cells characteristic of TNBs. Furthermore, short processes of ganglionic neurons extend caudally towards the aganglionic region, where telocytes in the TNB are located between the perineurium and nerve fibres into which they project telopodes. Thus, enteric ganglia within the TZ have abnormal structural characteristics, the cellular relationships of which are shared by the TNBs. These findings will help towards elucidation of the cellular mechanisms involved in the aetiology of Hirschsprung's disease.

Infantile hypertrophic pyloric stenosis (IHPS) is a common condition which presents with non-bilious vomiting and failure to thrive secondary to gastric outlet obstruction. In the UK, management is by fluid resuscitation followed by pyloromyotomy. Incomplete myotomy complicates 0.3% of cases necessitating further surgery and exposing the patient to further risk. Medical management of IHPS with antimuscarinics to promote pyloric relaxation is a well-described treatment modality that is used as first-line therapy in some countries. The use of this technique is limited by the need for extended hospital admission with parenteral nutrition administration. We describe a case of IHPS complicated by incomplete pyloromyotomy and subsequently managed successfully by atropine sulphate therapy.

The diagnostic uncertainty for children with abdominal pain has increased during the COVID-19 pandemic with the additional consideration of both COVID-19 and paediatric inflammatory multisystem syndrome—temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PIMS-TS) alongside appendicitis, mesenteric adenitis and other less common causes of abdominal pain. We describe the cases of two children who presented with severe abdominal pain, non-bilious vomiting and high temperatures during the UK’s first peak of the COVID-19 pandemic. Laboratory and abdominal ultrasound features were similar for both children but symptom progression in combination with cross-sectional abdominal imaging enabled differentiation between PIMS-TS and appendicitis with concurrent COVID-19. These cases highlight the importance of regular clinical review, multidisciplinary working and the utility of early cross-sectional imaging to determine the underlying condition.

N-methyl- d -aspartate (NMDA) receptor hypofunctionality is a well-studied hypothesis for schizophrenia pathophysiology, and daily dosing of the NMDA receptor co-agonist, d -serine, in clinical trials has shown positive effects in patients. Therefore, inhibition of d -amino acid oxidase (DAAO) has the potential to be a new therapeutic approach for the treatment of schizophrenia. TAK-831 (luvadaxistat), a novel, highly potent inhibitor of DAAO, significantly increases d -serine levels in the rodent brain, plasma, and cerebrospinal fluid. This study shows luvadaxistat to be efficacious in animal tests of cognition and in a translational animal model for cognitive impairment in schizophrenia. This is demonstrated when luvadaxistat is dosed alone and in conjunction with a typical antipsychotic. When dosed chronically, there is a suggestion of change in synaptic plasticity as seen by a leftward shift in the maximum efficacious dose in several studies. This is suggestive of enhanced activation of NMDA receptors in the brain and confirmed by modulation of long-term potentiation after chronic dosing. DAAO is highly expressed in the cerebellum, an area of increasing interest for schizophrenia, and luvadaxistat was shown to be efficacious in a cerebellar-dependent associative learning task. While luvadaxistat ameliorated the deficit seen in sociability in two different negative symptom tests of social interaction, it failed to show an effect in endpoints of negative symptoms in clinical trials. These results suggest that luvadaxistat potentially could be used to improve cognitive impairment in patients with schizophrenia, which is not well addressed with current antipsychotic medications.

Aims: Enteric nervous system (ENS) progenitor cells have been postulated to be an appropriate source of cells for the treatment of Hirschsprung’s disease. In order for this to be successful, the techniques previously used for the isolation of rodent ENS progenitor cells need to be adapted for postnatal human tissue. In this paper, we describe a method suitable for the preparation of both mouse and human postnatal ENS progenitor cells and assess their transplantation potential. Method: Single cell suspensions were isolated from 11.5 days post-coitum embryonic mouse caecum and postnatal human myenteric plexus. These cells were cultured under non-adherent conditions to generate neurospheres which were implanted into aganglionic embryonic mouse hindgut explants. Cell proliferation, migration and differentiation were observed using immunofluorescence microscopy. Results: Neurospheres generated from both mouse and human tissues contained proliferating neural crest-derived cells that could be expanded in tissue culture to generate both glial cells and neurons. When implanted into aganglionic murine gut, cells migrated from the neurospheres using pathways appropriate for cells derived from the neural crest, and differentiated to become glia and neurons expressing neuronal phenotypic markers characteristic of the ENS including nitric oxide synthase and vasoactive intestinal polypeptide. Conclusion: We have developed a technique for the isolation and expansion of ENS progenitor cells from human neonates. These cells have the ability to differentiate into neurons and glia when transplanted into aganglionic gut, this demonstration being a necessary first step for their autologous transplantation in the treatment of Hirschsprung’s disease.

Understanding the cellular anatomy of this region may aid in understanding the aetiology of HSCR and the effects of TZ pull-through on outcome, in addition to permitting the development of safe and effective use of ENS progenitor cells as therapy. Protein expression of ENS and neuronal markers (p75, SOX10, PHOX2b, Hu and GLUT1; Table 1) in ganglionic, proximal and distal TZ and aganglionic region of the bowel was visualised through immunofluorescence, and mRNA levels of the corresponding markers were quantified using qPCR. [...]due to the many complicated and varied post-transcriptional mechanisms involved in protein production from mRNA, there is potential for poor correlation between mRNA and protein expression, hence the potential for differing results between the methods.