Colorectal polyp classification and management of complex polyps for surgeon endoscopists.

Increasing familiarity with advanced endoscopic excision techniques allows for more colorectal lesions to be removed without major surgery. Endoscopic excision with negative margins is adequate for most polyps and low-risk T1 cancers. The use of modern polyp classification techniques based on size, morphology and pit pattern by an experienced endoscopist allow for an optical diagnosis of these lesions and can predict, with high accuracy, which lesions contain malignant disease and the level of invasion. A surgeon endoscopist must be able to recognize which complex polyps can be resected with advanced polypectomy techniques and which require upfront surgery. We aimed to provide an overview of polyp classification techniques to help surgeons select the correct treatment algorithm for advanced colorectal lesions based on their visual characteristics at index endoscopy.

Total neoadjuvant therapy for rectal cancer: a guide for surgeons.

The modern management of rectal cancers continues to evolve. With the release of data from new landmark randomized controlled trials (RAPIDO, PRODIGE-23), total neoadjuvant therapy (TNT) has moved to the forefront of locally advanced rectal cancer treatment and is considered a standard option in selected patients. Total neoadjuvant therapy promises enhanced systemic disease control, better treatment adherence and less time with an ostomy. However, TNT as currently described encompasses a number of different potential treatment options that differ significantly in terms of their radiation dosage, chemotherapy regimen and order of treatments administered. Being familiar with TNT regimens will be important for rectal cancer surgeons to appropriately advocate for their patients and optimize their outcomes. This article serves as a primer for the general surgeon and offers a pragmatic overview of the indications, realistic expected benefits and potential downsides of each TNT regimen.

Serrated polyps and polyposis of the colon: a brief review for surgeon endoscopists.

Serrated polyps (SPs) were once considered benign, clinically unimportant lesions. However, it is now recognized that through the serrated neoplasia pathway (SNP), SPs play a role in the development of 15%-30% of cases of colorectal cancers (CRC). Furthermore, a high proportion of postcolonoscopy CRCs are believed to arise from SNP. Serrated polyps are classified into hyperplastic polyps, sessile serrated lesions, sessile serrated lesions with dysplasia, traditionally serrated adenomas, and unclassified serrated adenoma, each with a distinct morphological and molecular profile. Despite improved understanding, SPs remain a clinical challenge owing to evolving terminology, frequent pathologic misclassification, endoscopic underdetection, and high rates of incomplete removal. Surgeon endoscopists and surgeons who perform colorectal procedures will undoubtedly come across patients with SPs, and this paper summarizes some of the clinical challenges they will encounter. We also discuss the diagnosis and management of patients with serrated polyposis syndrome (SPS).

TRPM8 activation attenuates inflammatory responses in mouse models of colitis.

Transient Receptor Potential Melastatin-8 (TRPM8), a recently identified member of the transient receptor potential (TRP) family of ion channels, is activated by mild cooling and by chemical compounds such as the supercooling agent, icilin. Since cooling, possibly involving TRPM8 stimulation, diminishes injury-induced peripheral inflammation, we hypothesized that TRPM8 activation may also attenuate systemic inflammation. We thus studied the involvement of TRPM8 in regulating colonic inflammation using two mouse models of chemically induced colitis. TRPM8 expression, localized immunohistochemically in transgenic TRPM8(GFP) mouse colon, was up-regulated in both human- and murine-inflamed colon samples, as measured by real-time PCR. Wild-type mice (but not TRPM8-nulls) treated systemically with the TRPM8 agonist, icilin showed an attenuation of chemically induced colitis, as reflected by a decrease in macroscopic and microscopic damage scores, bowel thickness, and myeloperoxidase activity compared with untreated animals. Furthermore, icilin treatment reduced the 2,4,6-trinitrobenzenesulfonic acid-induced increase in levels of inflammatory cytokines and chemokines in the colon. In comparison with wild-type mice, Dextran Sodium Sulfate (DSS)-treated TRPM8 knockout mice showed elevated colonic levels of the inflammatory neuropeptide calcitonin-gene-related peptide, although inflammatory indices were equivalent for both groups. Further, TRPM8 activation by icilin blocked capsaicin-triggered calcitonin-gene-related peptide release from colon tissue ex vivo and blocked capsaicin-triggered calcium signaling in Transient Receptor Potential Vaniloid-1 (TRPV1) and TRPM8 transfected HEK cells. Our data document an anti-inflammatory role for TRPM8 activation, in part due to an inhibiton of neuropeptide release, pointing to a novel therapeutic target for colitis and other inflammatory diseases.

Early Surveillance Endoscopy Should Be Performed Selectively After Transanal Endoscopic Microsurgery for Rectal Lesions.

Introduction Local recurrence (LR) rates after transanal endoscopic microsurgery (TEM) are unclear, and the utility of early postoperative surveillance for low-risk lesions is unknown. This study aimed to define LR after TEM for benign polyps and invasive adenocarcinoma, describe risk factors for LR, and evaluate the utility of early surveillance endoscopy. Methods This retrospective cohort study was conducted at two hospitals in Winnipeg, Manitoba, Canada. Adult patients who underwent TEM between 2009 and 2020 were evaluated for inclusion. The primary outcome was the rate of LR on surveillance endoscopy. Other outcomes included risk factors for LR and diagnostic yield of surveillance endoscopy. Results Among 357 patients who underwent TEM for benign polyps, LR was 10.5% (95% confidence interval (CI) 5.8-15.2) at three years. Positive margin was correlated with LR on multivariate analysis (hazard ratio (HR) 8.01, 95% CI 2.78-23.08). TEM defect closure was associated with lower LR on multivariate analysis (HR 0.19, 95% CI 0.06-0.59). Among 124 patients who underwent TEM for rectal adenocarcinoma, LR was 15.0% (95% CI 6.0-24.0) at three years. The first surveillance endoscopy had a 1.4% yield for low-risk patients (benign lesion, negative margins, and closed TEM defect) and 6.9% for all others. Conclusions LR at three years after TEM was 10.5% for benign polyps and 15.0% for adenocarcinomas. Early surveillance endoscopy can be considered low yield in some patients after TEM, which can be informative for shared decision-making regarding whether to proceed with early endoscopy in a low-risk subgroup of patients.

Implementation of Synoptic Reporting for Endoscopic Localization of Complex Colorectal Neoplasms.

Introduction  Lack of documented tattooing of colorectal neoplasms at index colonoscopy results in high repeat preoperative colonoscopy rates. We developed national consensus recommendations for endoscopic localization and piloted an electronic synoptic reporting template. We report on the implementation and perceptions of using synoptic reporting to enhance colorectal lesion marking in a central Canadian healthcare system.  Methods We implemented the template within our endoscopy reporting system and ran an infographic education campaign. We then conducted a follow-up email-based interview with all regional endoscopists. Thematic analysis and a mixed-methods triangulation approach were employed to synthesize qualitative and quantitative data.  Results The interview was completed by 28/52 endoscopists (54%). Most (60.7%; n = 17) completed >100 colonoscopies and 71.4% (n = 20) identified six to 20 neoplasms requiring tattooing since introduction. A total of 50% (n = 14) used the template. Those not using it were unaware of it (42.9%; n = 12), or preferred using narrative text (17.9%; n = 5). Users reported modest mean functionality scores (intuitiveness: 3.56/5; efficiency: 3.7/5) and high impact scores (credible: 4.22/5; informative: 4.21/5). However, the perception of the synoptic template's ability to reduce the repeat preoperative colonoscopy rate was more circumspect (3.76/5). Conclusions Endoscopists believed the synoptic template was a functional, impactful tool that would improve communication and help to decrease the repeat preoperative colonoscopy rate. However, synoptic template uptake was limited by provider awareness, therefore more educational efforts are needed to increase uptake.

The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis.

Merlin, the protein product of the Neurofibromatosis type-2 gene, acts as a tumour suppressor in mice and humans. Merlin is an adaptor protein with a FERM domain and it is thought to transduce a growth-regulatory signal. However, the pathway through which Merlin acts as a tumour suppressor is poorly understood. Merlin, and its function as a negative regulator of growth, is conserved in Drosophila, where it functions with Expanded, a related FERM domain protein. Here, we show that Drosophila Merlin and Expanded are components of the Hippo signalling pathway, an emerging tumour-suppressor pathway. We find that Merlin and Expanded, similar to other components of the Hippo pathway, are required for proliferation arrest and apoptosis in developing imaginal discs. Our genetic and biochemical data place Merlin and Expanded upstream of Hippo and identify a pathway through which they act as tumour-suppressor genes.

Mechanisms behind the anti-inflammatory actions of insulin.

The epidemic of diabetes mellitus is worsening worldwide. Diabetes mellitus is a chronic metabolic disease characterized by inappropriate recurrent or persistent hyperglycemia. Numerous studies have demonstrated that hyperglycemia, the most significant predictor of poor clinical outcome in diabetes mellitus patients, can directly promote an inflammatory response and oxidative stress. Although there are various causes of DM, all eventually lead to absolute or relative insulin deficiency and death of pancreatic ß-cells. Thus, insulin inevitably becomes the primary medication used to treat the disease and prevent diabetic complications in all DM patients. Interestingly, an emerging body of evidence suggests that insulin suppresses the inflammatory process, not only through preventing hyperglycemia but also by modulating key inflammatory molecules. In this review, we discuss the findings of studies done in vitro as well as clinical trials that have demonstrated an anti-inflammatory action of insulin and that have pointed to mechanisms responsible for this effect. Further, we discuss how the anti-inflammatory action of insulin bears on our current understanding of the pathophysiology and complications of both type 1 and type 2 diabetes.

Insulin modulates protease-activated receptor 2 signaling: implications for the innate immune response.

Given the anti-inflammatory effects of insulin in human and animal studies done in vivo and given the signaling pathways in common between insulin and the protease-activated receptor 2 (PAR(2)), a G protein-coupled receptor, we hypothesized that insulin would have an impact on the inflammatory actions of PAR(2). We found that low doses or concentrations of insulin in the subnanomolar range reduced PAR(2)-induced inflammation in a murine paw edema model, attenuated PAR(2)-induced leukocyte trafficking in mouse intestinal venules, and reduced PAR(2) calcium signaling in cultured dorsal root ganglion neurons and endothelial cells. This effect of insulin to attenuate PAR(2)-mediated inflammation was reversed when cells were preincubated with LY294002 (a PI3K inhibitor) and GF 109203X (a pan-protein kinase C inhibitor). The enhanced inflammatory effect of PAR(2) observed in vivo in an insulin-deficient murine type 1 diabetes model was attenuated by the local administration of insulin at the inflammatory site. Our data point to an anti-inflammatory action of insulin that targets the acute innate inflammatory response triggered by PAR(2).

Rectal Cancer Metastasis to the Anal Verge: An Unusual Case Presentation and Review of the Literature.

BACKGROUND: Anal metastasis of colorectal adenocarcinoma is very rare, represented by only a handful of case reports in the literature. Previously, reports of metastasis to this region had occurred following a history of anorectal disease, such as anal fistulae. Antecedent trauma to the area from hemorrhoidectomy, fissures, or perineal retractor injury have also been implicated. CASE PRESENTATION: Herein we report the case of 69-year-old man without any history of anal disease presenting with a metachronous metastasis of a colorectal-type adenocarcinoma to the anal verge. He was previously treated for T1N0 rectal adenocarcinoma at the rectosigmoid junction with a low anterior resection 5 years prior, then had a T3N0 local recurrence at the colorectal anastomosis treated with neoadjuvant chemoradiation, and eventually a Hartmann's procedure 4 years later. Subsequently, on surveillance flexible sigmoidoscopy, a new tumor was identified on the perianal skin extending from the anal verge. Histopathology demonstrated colorectal-type adenocarcinoma. Flexible endoscopy identified no other residual or recurrent disease in the colon or rectal stump. The patient was treated with wide local excision and advancement flap reconstruction. CONCLUSION: Isolated metastasis to the anus is an extremely rare occurrence for colorectal adenocarcinoma. There exists little evidence to inform management. One option is to treat like a locally recurrent rectal cancer with aggressive tri-modality management consisting of chemoradiation, abdominal perineal resection, and adjuvant chemotherapy. In the absence of metastatic disease, local resection and close surveillance remain an option. As always, patient factors should guide management.

Ruptured Middle Colic Artery Aneurysm Presenting with Symptoms of Acute Cholecystitis: A Case Report and Literature Review.

Background: Ruptured middle colic artery aneurysm is extremely uncommon. Diagnosis can be challenging, as symptomatology can be attributed to more common abdominal pathologies. Due to the rarity of this condition, only case reports are available to inform management. Case Presentation: We present the case of a 72-year-old woman with a ruptured middle colic artery aneurysm presenting with signs and symptoms more suggestive of acute calculous cholecystitis. Her co-existing bleed was confirmed on CT angiogram. Coil embolization was initially attempted unsuccessfully. She underwent laparotomy, a middle colic artery ligation, and extended right hemicolectomy with intra-aortic balloon placement for emergency proximal vascular control. Post-operatively, she had a re-bleed that was successfully managed with covered stent placement in the proximal superior mesenteric artery after an unsuccessful re-attempt at coil embolization. Her apparent associated cholecystitis was managed with antibiotics and resolved uneventfully. Conclusion: A middle colic artery aneurysm can be challenging to diagnose and treat. Management options include endovascular techniques, open surgery, or a combination approach. Intra-aortic balloon placement for emergency vascular control is a novel approach that could avoid hemorrhage when intra-abdominal vascular access is challenging.

Routine pathologic evaluation of circular stapler anastomotic rings is not useful after resection for colorectal cancer: retrospective study and systematic review with meta-analysis.

BACKGROUND: Circular staplers are commonly used for reconstruction after radical resection for colorectal cancer. Pathological analysis of the anastomotic rings is common practice, although the benefits are unclear. The purpose of this study was to evaluate the usefulness of routine histopathological analysis of anastomotic rings in an original series and in a systematic review of the literature. METHOD: The retrospective study was performed at two university-associated academic hospitals in Winnipeg, Canada, including patients investigated for colorectal cancers (within 30 cm of the anal verge) who underwent resection between 2007 and 2020. The systematic review involved Ovid MEDLINE, Embase, Scopus, and Web of Science databases, selecting for adult human studies involving analysis of anastomotic rings in elective colorectal cancer resections. The main outcome measure was the proportion of patients with cancer in the anastomotic ring specimens. The frequency of benign pathology findings and changes to patient management were also examined. RESULTS: Out of 673 eligible patients, 487 were included in the retrospective analysis. No patients had cancer within the anastomotic ring specimens. Twenty-five patients (5.1 per cent) had benign pathological findings within the anastomotic ring specimens, and patient management was never affected. In the systematic review, 27 articles were included in the final analysis out of 5848 records reviewed. The rate of cancer within anastomotic ring specimens was 0.34 per cent, and the rate of change in patient management was 0.19 per cent. CONCLUSION: The likelihood of finding cancer within anastomotic rings is rare and their histopathological examination seldom changes patient management.

A Strangulated Meckel's Diverticulum in an Inguinal Hernia: A Case Report and Literature Review.

BACKGROUND: Meckel's diverticulum is an embryologic remnant of the vitelline duct, occurring in approximately 2% of the adult population. A hernia containing a Meckel's diverticulum is called a Littré's hernia and is rarely reported in the medical literature. Clinically, a Littré's hernia is indistinguishable from a hernia containing small bowel and is often discovered incidentally during a repair. CASE PRESENTATION: Herein, we report a rare case of strangulated Littré's hernia in a patient's right groin. The sac contained a long segment of small bowel in addition to a large Meckel's diverticulum. The bowel was irreducible through the groin incision, and a lower midline laparotomy was made. Necrotic bowel including the Meckel's diverticulum was resected. Given the presence of necrotic bowel and potential for infection, the hernia was repaired with a Bassini herniorrhaphy, reinforced with absorbable mesh. The patient recovered uneventfully. CONCLUSION: Littré's hernia is a rare clinical entity. Treatment is similar to any bowel-containing hernia. Repair of the hernia defect with permanent mesh should be weighed against the risk of implant infection.

Contribution of bone marrow-derived cells to the pro-inflammatory effects of protease-activated receptor-2 in colitis.

OBJECTIVE: Our aim was to determine the contribution of proteinase-activated receptor-2 (PAR(2))-expressing bone marrow-derived cells on the development of colonic inflammation. MATERIALS: Chimeric mice were generated by injecting bone marrow cells from wildtype (PAR (2) (+/+) ) or PAR(2) knockout mice (PAR (2) (-/-) ) into irradiated PAR (2) (+/+) or PAR (2) (-/-) mice. TREATMENTS: Colitis was induced by giving 2.5% dextran sodium sulfate (DSS) solution for 7 days or by a single intracolonic administration of trinitrobenzene sulphonic acid (TNBS, 2 mg dissolved in 40% ethanol). METHODS: Seven days after the induction of colitis, bowel thickness, inflammatory parameters [myeloperoxidase (MPO) activity, macroscopic/microscopic damage scores], and leukocyte trafficking (visualized via intravital microscopy) were assessed. RESULTS: Total deficiency of PAR(2) resulted in a marked reduction in severity of both TNBS and DSS induced colitis as assessed by MPO activity, macroscopic damage, bowel thickness, and leukocyte adherence. Colitis was attenuated in all chimeric lines in which there was loss of PAR(2) in the host, non-bone marrow-derived tissue, independent of the status of PAR expression by bone marrow-derived cells. Interestingly, TNBS colitis was attenuated in PAR (2) (+/+) chimeric mice with PAR (2) (-/-) derived bone marrow but these animals were not protected from DSS colitis. CONCLUSIONS: Expression of PAR(2) by host-derived tissues plays a dominant role in regulating colonic inflammation. PAR(2) expression by bone marrow-derived cells appears to play a role in TNBS colitis but not in DSS induced injury.

Derivatized 2-furoyl-LIGRLO-amide, a versatile and selective probe for proteinase-activated receptor 2: binding and visualization.

The proteinase-activated receptor-2 (PAR2)-activating peptide with an N-terminal furoyl group modification, 2-furoyl-LIGRLO-NH2 (2fLI), was derivatized via its free ornithine amino group to yield [3H]propionyl-2fLI and Alexa Fluor 594-2fLI that were used as receptor probes for ligand binding assays and receptor visualization both for cultured cells in vitro and for colonic epithelial cells in vivo. The binding of the radiolabeled and fluorescent PAR2 probes was shown to be present in PAR2-transfected Kirsten normal rat kidney cells, but not in vector-alone-transfected cells, and was abolished by pretreatment of cells with saturating concentrations of receptor-selective PAR2 peptide agonists such as SLIGRL-NH2 and the parent agonist 2fLI but not by reverse-sequence peptides such as 2-furoyl-OLRGIL-NH2 that cannot activate PAR2. The relative orders of potencies for a series of PAR2 peptide agonists to compete for the binding of [3H]propionyl-2fLI (2fLI >> SLIGRL-NH2 approximately= trans-cinnamoyl-LIGRLO-NH2 > SLIGKV-NH2 > SLIGKT-NH2) mirrored qualitatively their relative potencies for PAR2-mediated calcium signaling in the same cells or for vasorelaxation in a rat aorta vascular assay. In the vascular assay, the potency of Alexa Fluor 594-2fLI was the same as 2fLI. We conclude that ornithine-derivatized 2fLI peptides are conveniently synthesized PAR2 probes that will be of value for future studies of receptor binding and visualization.

Anti-inflammatory effects of nitric oxide-releasing hydrocortisone NCX 1022, in a murine model of contact dermatitis.

1 The concept that nitric oxide (NO) release can be beneficial in inflammatory conditions has raised more attention in the recent years, particularly with the development of nitric oxide-releasing anti-inflammatory drugs. There is considerable evidence that NO is capable of enhancing the anti-inflammatory benefits of conventional anti-inflammatory drugs. 2 Since hydrocortisone is the most widely used anti-inflammatory drug for the treatment of skin inflammation, we compared the anti-inflammatory effects of hydrocortisone to an NO-releasing derivative of hydrocortisone, NCX 1022, in a murine model of irritant contact dermatitis, induced by epidermal application of benzalkonium chloride. 3 Topical pre- and post-treatment with NCX 1022 (3 nmol) in C57BL6 mice not only reduced ear oedema formation in a dose-dependent manner, but also was significantly more effective than the parent compound during the initial stages of inflammation (from 1 to 5 h). NCX 1022, but not hydrocortisone, significantly inhibited granulocyte recruitment (tissue myeloperoxidase activity). Histological samples of mouse ears treated with NCX 1022 showed significant reduction in both the number of infiltrated cells and disruption of the tissue architecture compared to hydrocortisone-treated tissues. 4 With intravital microscopy, we observed that both pre- and post-treatments with NCX 1022 were more effective than hydrocortisone in terms of inhibiting benzalkonium chloride-induced leukocyte adhesion to the endothelium, without affecting the flux of rolling leukocytes or venule diameter. 5 These results suggest that by releasing NO, NCX 1022 modulates one of the early events of skin inflammation: the recruitment of leukocytes to the site of inflammation. Overall, we have shown that NO-hydrocortisone provided faster and greater protective effects, reducing major inflammatory parameters (leukocyte adhesion and recruitment, oedema formation, tissue disruption) compared to its parental compound.

The Role of Lung Lobes in Radiation Pneumonitis and Radiation-Induced Inflammation in the Lung: A Retrospective Study.

OBJECTIVE: We examined the relative response to radiation of the upper lung lobes (UL) versus lower lung lobes (LL) of normal lung tissue using normalized [18F]-fluorodeoxyglucose (FDG) uptake per radiation dose received per lung voxel in patients treated with either photons or protons and tested for correlation of the radiation response with clinical pneumonitis. METHODS: Seventy-five patients (photon (n = 51) or proton (n = 24)) treated for esophageal cancer from November 1, 2003 to May 15, 2011 who received restaging FDG-positron emission tomography (PET) imaging 1 to 3 months after chemoradiation were selected. UL and LL were contoured using the major fissure as the boundary, with the right middle lobe being included in the right UL structure. Pneumonitis toxicity was scored using the Common Terminology Criteria for Adverse Events, version 4.0 based on the consensus of 5 clinicians. RESULTS: LL had a higher mean dose (15.6 Gy vs. 10.4 Gy, p<0.001), higher mean standard uptake value (SUV) (0.78 vs. 0.56, p=0.001) and SUV in low dose regions (0.80 vs. 0.66 for 10 to 20 Gy, p=0.001), and lower mean dose response (0.015 vs. 0.019, p=0.003) compared to the UL. The mean dose ratio of UL vs. LL (p < 0.001), and SUV in the region of lung receiving 0-10 Gy (p=0.04), but not the dose response ratio of UL vs. LL (p=0.53) correlated with symptomatic pneumonitis. CONCLUSION: Upper lung lobes had a greater pulmonary metabolic radiation response than lower lung lobes. Greater dose to UL relative to LL and higher SUV in the low dose region (10-20 Gy) on post-treatment PET correlated with symptomatic pneumonitis.

Protective effect of proteinase-activated receptor 2 activation on motility impairment and tissue damage induced by intestinal ischemia/reperfusion in rodents.

We hypothesized that proteinase-activated receptor-2 (PAR(2)) modulates intestinal injuries induced by ischemia/reperfusion. Ischemia (1 hour) plus reperfusion (6 hours) significantly delayed gastrointestinal transit (GIT) compared with sham operation. Intraduodenal injection of PAR(2)-activating peptide SLIGRL-NH(2) significantly accelerated transit in ischemia/reperfusion but not in sham-operated rats. GIT was significantly delayed in ischemia/reperfusion and sham-operated PAR(2)(-/-) mice compared with PAR(2)(+/+). SLIGRL-NH(2) significantly accelerated transit in ischemia/reperfusion in PAR(2)(+/+) but not in PAR(2)(-/-) mice. Prevention of mast cell degranulation with cromolyn, ablation of visceral afferents with capsaicin, and antagonism of calcitonin gene-related peptide (CGRP) and neurokinin-1 receptors with CGRP(8-37) and RP67580, respectively, abolished the SLIGRL-NH(2)-induced stimulatory effect on transit in ischemia/reperfusion. Tissue damage was significantly reduced by SLIGRL-NH(2); this effect was not observed in cromolyn-, capsaicin-, or RP67580-treated rats but was detected following CGRP(8-37). Intestinal PAR(2) mRNA levels were not affected by SLIGRL-NH(2) in ischemia/reperfusion. We propose that PAR(2) modulates GIT and tissue damage in intestinal ischemia/reperfusion by a mechanism dependent on mast cells and visceral afferents. PAR(2) effect on transit might be mediated by CGRP and substance P, whereas the effect on tissue damage appears to involve substance P but not CGRP. PAR(2) might be a signaling system in the neuroimmune communication in intestinal ischemia/reperfusion.

ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology.

Spinocerebellar ataxia type 1 (SCA1) is one of several neurodegenerative diseases caused by expansion of a polyglutamine tract in the disease protein, in this case, ATAXIN-1 (ATXN1). A key question in the field is whether neurotoxicity is mediated by aberrant, novel interactions with the expanded protein or whether its wild-type functions are augmented to a deleterious degree. We examined soluble protein complexes from mouse cerebellum and found that the majority of wild-type and expanded ATXN1 assembles into large stable complexes containing the transcriptional repressor Capicua. ATXN1 directly binds Capicua and modulates Capicua repressor activity in Drosophila and mammalian cells, and its loss decreases the steady-state level of Capicua. Interestingly, the S776A mutation, which abrogates the neurotoxicity of expanded ATXN1, substantially reduces the association of mutant ATXN1 with Capicua in vivo. These data provide insight into the function of ATXN1 and suggest that SCA1 neuropathology depends on native, not novel, protein interactions.