Use of 3D-CT-derived psoas major muscle volume in defining sarcopenia in colorectal cancer.

BACKGROUND: Sarcopenia is characterized by reduced skeletal muscle volume and is a condition that is prevalent among elderly patients and associated with poor prognosis as a comorbidity in malignancies. Given the aging population over 80 years old in Japan, an understanding of malignancies, including colorectal cancer (CRC), complicated by sarcopenia is increasingly important. Therefore, the focus of this study is on a novel and practical diagnostic approach of assessment of psoas major muscle volume (PV) using 3-dimensional computed tomography (3D-CT) in diagnosis of sarcopenia in patients with CRC. METHODS: The subjects were 150 patients aged ≥ 80 years with CRC who underwent primary tumor resection at Juntendo University Hospital between 2004 and 2017. 3D-CT measurement of PV and conventional CT measurement of the psoas major muscle cross-sectional area (PA) were used to identify sarcopenia (group S) and non-sarcopenia (group nS) cases. Clinicopathological characteristics, operative results, postoperative complications, and prognosis were compared between these groups. RESULTS: The S:nS ratios were 15:135 for the PV method and 52:98 for the PA method. There was a strong positive correlation (r = 0.66, p < 0.01) between PVI (psoas major muscle volume index) and PAI (psoas major muscle cross-sectional area index), which were calculated by dividing PV or PA by the square of height. Surgical results and postoperative complications did not differ significantly in the S and nS groups defined using each method. Overall survival was worse in group S compared to group nS identified by PV (p < 0.01), but not significantly different in groups S and nS identified by PA (p = 0.77). A Cox proportional hazards model for OS identified group S by PV as an independent predictor of a poor prognosis (p < 0.05), whereas group S by PA was not a predictor of prognosis (p = 0.60). CONCLUSIONS: The PV method for identifying sarcopenia in elderly patients with CRC is more practical and sensitive for prediction of a poor prognosis compared to the conventional method.

Sortilin acts as an endocytic receptor for α-synuclein fibril.

Cell-to-cell spreading of misfolded α-synuclein (αSYN) is supposed to play a key role in the pathological progression of Parkinson's disease (PD) and other synucleinopathies. Receptor-mediated endocytosis has been shown to contributes to the uptake of αSYN in both neuronal and glial cells. To determine the receptor involved in αSYN endocytosis on the cell surface, we performed unbiased, and comprehensive screening using a membrane protein library of the mouse whole brain combined with affinity chromatography and mass spectrometry. The candidate molecules hit in the initial screening were validated by co-immunoprecipitation using cultured cells; sortilin, a vacuolar protein sorting 10 protein family sorting receptor, exhibited the strongest binding to αSYN fibrils. Notably, the intracellular uptake of fibrillar αSYN was slightly but significantly altered, depending on the expression level of sortilin on the cell surface, and time-lapse image analyses revealed the concomitant internalization and endosomal sorting of αSYN fibrils and sortilin. Domain deletion in the extracellular portion of sortilin revealed that the ten conserved cysteines (10CC) segment of sortilin was involved in the binding and endocytosis of fibrillar αSYN; importantly, pretreatment with a 10CC domain-specific antibody significantly hindered αSYN fibril uptake. The presence of sortilin in the core structure of Lewy bodies and glial cytoplasmic inclusions in the brain of synucleinopathy patients was confirmed via immunohistochemistry, and the expression level of sortilin in mesencephalic dopaminergic neurons may be altered with disease progression. These results provide compelling evidence that sortilin acts as an endocytic receptor for pathogenic form of αSYN, and yields important insight for the development of disease-modifying targets for synucleinopathies.

pfeRNAs-A Novel Class of Small Non-coding RNAs With Real Translational Potential.

Small non-coding RNAs (sncRNAs) are defined by being less than 200 nucleotides (nt) in length, and consequently, have been divided into many different subclasses including mature microRNA (miRNA), small interfering RNA (siRNA), piwi-interacting RNA (piRNA), protein functional effector sncRNA (pfeRNA), precursor miRNA (pre-miRNA), small nucleolar RNA (snoRNA), 5S ribosome RNA (5SrRNA), 5.8SrRNA, and small nuclear RNA (snRNA). Except for the class of pfeRNAs, the discovery, identification, biogenesis, characterization, and function of other sncRNAs have been well documented. Herein, we provide a review, written especially for clinicians, of the least understood class of functional sncRNAs, the pfeRNAs, focusing on their initial discovery, identification, unique features, function, as well as their exciting clinical translational potential.

Examination of colorectal cancer cases with metal allergy.

PURPOSE: To report our initiatives and treatment results for patients with colorectal cancer with metal allergy. METHODS: A total of 27 patients (2.6%) with a history of metal contact dermatitis were identified among 1027 patients who underwent curative resection of colorectal cancer from 2014 to 2020. The results of the patch test, perioperative results, and postoperative colonoscopy findings were also investigated. RESULTS: The patch test for metal allergens and staples was performed in 21 patients (77.8%), and 13 of them (61.9%) tested positive for at least one metal allergen. Ni (38.1%), Co (28.6%), and Pd (19.0%) showed higher positive rates than other metals, and 1 patient (4.8%) tested positive for staples. Stapled anastomosis/suturing was performed as planned in 15 of 27 patients. In 10 patients, the anastomosis method was changed from stapled to hand-sewn according to the no-patch test results (60%), positivity for multiple metals (20%), positivity for staples (10%), and surgeon's judgment (10%). No complications and abnormal colonoscopy findings were found to be associated with stapled anastomosis/suturing. CONCLUSION: The patch test is useful for selecting an optimal anastomosis method for patients with suspected metal allergy.

Prenatal stress enhances atherosclerosis and telomere shortening in ApoE knockout mouse offspring.

Children born to women who experience stress during pregnancy have an increased risk of atherosclerosis in later life, but few animal models have explored mechanisms. To study this phenomenon, timed-bred ApoE knockout mice were determined pregnant with ultrasound and randomly assigned on gestation day 8.5 to either a control (no stress) or prenatal stress (PS) group using 2 h of restraint for five consecutive days. PS significantly increased plasma corticosterone levels in pregnant mice. The litters from PS mice showed increased neonatal mortality within the first week of life. Body weights (at euthanasia) of adult offspring at 25 wk from the PS group were significantly increased compared with weights of controls. Adult offspring from these pregnancies were serially imaged with ultrasound to measure plaque thickness and were compared with plaque macroscopic and microscopic pathology. PS groups had increased plaque thickness determined by ultrasound, gross, histological evaluation and increased aortic root and valve macrophage infiltration at 25 wk. Five-week-old mice from PS group had significant decrease in mean arterial pressure, yet blood pressure normalized by 10 wk. As prenatal stress induced increased atherosclerosis, and telomeres are susceptible to stress, aortas from 10-wk-old mice were compared for telomere lengths and were found to be significantly shorter in PS mice compared with control mice. These studies support future investigation of how stress impacts telomere shortening in animal models and human aortas. This model could be further used to investigate the role of prenatal stress, telomere biology, and atherosclerosis pathogenesis in adults.

Efficacy and safety of regorafenib dose-escalation therapy for Japanese patients with refractory metastatic colorectal cancer (RECC study).

BACKGROUND: Regorafenib significantly improves overall survival in previously treated metastatic colorectal cancer patients. However, various toxicities, such as hand-foot skin reaction (HFSR), fatigue, and liver dysfunction have limited the use of regorafenib. These toxicities appear soon after treatment initiation. The ReDOS study demonstrated the effectiveness of a weekly dose-escalation therapy of regorafenib starting with a lower daily dose; however, its usefulness in Asian subjects is unknown. We conducted a phase II study to evaluate the safety and survival benefit of regorafenib dose-escalation therapy for Japanese patients. METHODS: Patients with sufficient organ function, who had previously received more than two lines of chemotherapy were included. Regorafenib was started at 80 mg/day and escalated to 120 mg/day in Week 2 and 160 mg/day in Week 3, if no severe drug-related toxicities were observed. The primary endpoint was cancer progression-free survival (PFS). Tumor response and progression were assessed radiologically every 8 weeks. This study was registered in the University Hospital Medical Information Network (UMIN#UMIN000028933). RESULTS: 57 patients were enrolled and all started regorafenib at 80 mg/day. 32 patients (56.1%) were subsequently escalated to 120 mg/day and 19 (33.3%) to 160 mg/day. Only 8 patients (14.0%) discontinued treatment because of adverse events. Median PFS was 1.9 months. Median overall survival was 8.9 months, the response rate was 0%, and the disease control rate was 31.6%. The most frequent adverse event greater than grade 3 was hypertension (19.3%), followed by HFSR (14.0%). CONCLUSIONS: Regorafenib dose-escalation therapy is well tolerated with PFS-like regorafenib standard therapy.

[A Case of Recurrence in the Abdominal Wall and Perineal Region of Rectal Cancer Successfully Treated with Minimally Invasive Surgery and Radiation Therapy].

Local recurrence after rectal cancer surgery is often difficult to treat because there are few effective treatments. In this study, we report a case of parastomal and perineal recurrence after Miles' surgery in an elderly patient who had a favorable outcome after laparoscopic surgery and radiation therapy. Our results suggest that a combination of minimally invasive treatment may be effective in elderly patients and after polysurgery.

[A Case Report of a Giant GIST Markedly Responsive to Neoadjuvant Chemotherapy with Imatinib Mesylate].

Male in his 50s complaining of abdominal pain was referred to our hospital. Abdominal CT scan showed a giant tumor which had diameter of approximately 50 mm in lower rectum. A biopsy specimen was positive for CD34 and c-kit. Based on these findings, it was diagnosed as gastrointestinal stromal tumor(GIST). We treated the patient with neoadjuvant therapy using imatinib mesylate(IM)to reduce the tumor size and to avoid the extensive surgery. The patient started to take IM at a daily dose of 400 mg. After 3 months, CT and MRI revealed that the tumor size decreased(40% reduction). We performed the robot assisted intersphincteric resection(ISR). Although it has been 28 months since the surgery, there are no obvious signs of recurrence. A patient diagnosed with giant GIST could avoid an extensive surgery due to neoadjuvant therapy with IM.

Prenatal stress enhances NNK-induced lung tumors in A/J mice.

Children born to women who experience stress during pregnancy have an increased risk of cancer in later life, but no previous animal studies have tested such a link. We questioned whether prenatal stress (PS) in A/J mice affected the development of lung tumors after postnatal response to tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Timed-bred A/J mice were randomly assigned on gestation day 12.5 to PS by restraint for 5 consecutive days or control (no restraint). Adult offspring of control and stressed pregnancies were all treated with three NNK injections (50 mg/kg every other day) and euthanized 16 weeks later to examine their lungs. Compared with controls, PS dams exhibited significantly increased levels of plasma corticosterone, increased adrenal weights and decreased fetus weights without fetal loss. Prenatally stressed litters had a significantly higher neonatal death rate within first week of life, and surviving male and female offspring developed lung epithelial proliferations with increase multiplicity, increased area and aggressive morphology. PS also induced more advanced atypical adenomatous hyperplasia lesions. We found no difference in lung NNK-derived methyl DNA adducts, but PS did significantly enhance CD3+ T cell and Foxp3+ T cell tumor infiltration. PS significantly increases multiplicity, area of NNK-induced lung tumors and advanced morphology. PS did not affect production of NNK-derived methyl DNA adducts but did increase lymphocytic infiltration of lung tumors. To our knowledge, this is the first animal model of PS with evaluation of cancer development in offspring.

[A Case of Good Quality of Life(QOL)and Favorable Response to Transarterial Chemoembolization(TACE)against Synchronous Multiple Liver Metastases].

We report a case of good quality of life(QOL)and favorable response to transarterial chemoembolization(TACE)against synchronous multiple liver metastases. An 85-year-old man was admitted to our hospital because of melena. Colonoscopy showed multiple type 2 tumors in the sigmoid colon and upper rectum. CT and EOB-MRI examinations revealed that there were multiple liver metastases. Because of his age and surgical stress, he underwent a laparoscopic Hartmann's procedure. After the resection of the primary tumor, he received tegafur/uracil for his liver metastases. However, he discontinued receiving the drugs 2 weeks later because of the development of adverse events. Instead of systemic chemotherapy, he chose to undergo TACE. He underwent TACE with irinotecan and HepaSphereTM(BioSphere Medical)8 times for his multiple liver metastases. Consequently, all multiple liver metastases disappeared. Therefore, TACE may be useful for patients who are not suitable for systemic chemotherapy.

[A Case of Systemic Chemotherapy Combined with Molecular Drug Treatment Following Biliary Stent Implantation for Obstructive Jaundice Due to Metastases of Liver Gland Lymph Node after Colorectal Cancer Surgery].

We report a case of systemic chemotherapy after biliary stent placement for obstructive jaundice due to hepatic portal lymph node metastasis after colorectal cancer surgery. The patient was a 40s woman. Laparoscopic anterior resection for rectosigmoidRS cancer was performed. The pathological diagnosis was T3N0M0PUL0R0, pStage Ⅱ according to the 8th edition of colorectal cancer handling regulations. Because multiple liver metastases were observed 8 months after the surgery, partial resection of the posterior region of the liver was performed. Multiple lung metastases were observed 1 year after hepatectomy, but she wantedto undergo follow-up observation. Jaundice was observed 1 year after the diagnosis of lung metastasis, and obstructive jaundice due to hepatic portal lymph node metastasis was diagnosed. Endoscopic retrograde biliary drainage(ERBD)was performed, and a bile duct stent was placed. After improving jaundice, 12 courses of mFOLFOX6 plus cetuximab therapy were performed. Currently, because of the exacerbation of lung metastasis, FOLFIRI plus bevacizumab therapy is being administered. Systemic chemotherapy containing a molecular-targeted drug is being administered in our case, but complications relatedto the biliary stent have not been observed. There are few reports on similar cases, andfollow - up observation with careful attention to long-term safety is necessary.

Endoscopic Submucosal Dissection Decreases Additional Colorectal Resection for T1 Colorectal Cancer.

BACKGROUND There are 3 methods of treating T1 colorectal cancer (T1 CRC), which include endoscopic resection, endoscopic resection followed by additional colorectal resection, and surgical resection. In this retrospective study, changes in the management of T1 CRC after introduction of endoscopic submucosal dissection (ESD) were investigated by comparison with the 10-year period before introduction of ESD. MATERIAL AND METHODS During a 20-year period from 1996 to 2015, 835 patients with T1 CRC were treated, including 331 patients before introduction of ESD (Group A) and 504 patients after introduction of ESD (Group B). Clinicopathological findings and treatment methods were compared between these 2 groups. RESULTS As the initial treatment, endoscopic treatment was performed in 185 patients (55.9%) in Group A and 288 (57.1%) in Group B. In Group B, ESD was performed in 161 patients (55.9%), accounting for more than half of the T1 CRC patients receiving endoscopic treatment. In Groups A and B, observation after endoscopic resection was selected for 54.2% and 67.3% of T1a patients, respectively (p=0.04). A similar trend was noted for T1b patients, and there was no significant difference of the treatment approach. Among all T1 CRC patients, the percentage undergoing observation after endoscopic resection was significantly higher in Group B than in Group A (34.3% vs. 26.9%, p=0.02), and the percentage of patients undergoing additional colorectal resection was significantly lower in Group B (22.8% vs. 29.0%, p=0.04). CONCLUSIONS After introduction of ESD, it was performed in more than half of all patients with T1 CRC undergoing endoscopic treatment. The percentage of patients undergoing observation following endoscopic resection of T1 CRC increased after introduction of ESD.

[A Study of Treatment for Pathological T1(SM)Colorectal Cancer Patients after Endoscopic Resection at Our Department].

Approximately 10% of pathological T1(SM)colorectal cancer patients develop lymph node metastases. Therefore additional colectomy with lymph node dissection is recommended when it applies to the specific criteria in the current JSCCR guidelines. However, additional colectomy would not be done in some cases, because surgery is too invasive for some patients. Endoscopic treatment(ESD or EMR)for T1(SM)cancer was performed in 324 cases between 2008 and 2016. Of those, 231 cases had satisfied the criteria for additional colectomy. Among them, 74 cases(32.0%)did not undergo, and additional colectomy(+)groupwas 153 cases(66.2%). Between the 2 groups, no difference in prognosis could be found. We considered there was no difference, because the prognosis of SM cancer is relatively good. In consideration of patient background, the treatment policy has to be chosen according to feasibility.

[A Case of Pelvic Metastasis of Rectal Cancer That Developed Ten Years after Curative Resection].

We report a case of pelvic metastasis of rectal cancer that developed 10 years after curative resection. An 81-year-old woman underwent intersphincteric resection for lower rectal cancer 10 years previously. The tumor was pathologically diagnosed as T2N0M0, Stage Ⅰ. Nine years after the curative resection, serum carcinoembryonic antigen(CEA)levels were slightly elevated, but no recurrence was found on computed tomography(CT). Eleven months after CT, serum CEA levels elevated to 15.9 ng/mL. Pelvic metastasis in the piriformis muscle was detected on positron emission tomography(PET)-CT. Following CT-guided biopsy, she was pathologically diagnosed with metastatic rectal cancer. Radiotherapy (60 Gy/30 Fractions) was administered. Ten months after radiotherapy, PET-CT revealed no relapse in the pelvis with lung metastases.

A case of total laparoscopic sigmoidectomy involving the use of needle forceps and transanal specimen extraction for sigmoid colon cancer.

A 76-year-old male underwent endoscopic mucosal resection for a stage T1 tumour of the sigmoid colon. We performed laparoscopic sigmoidectomy through 5 ports using needlescopic instruments. The resected specimen was extracted from the abdominal cavity transanally. After attaching an anvil to the sigmoidal stump, the rectal stump was reclosed using an endoscopic linear stapler, and then, colorectal anastomosis was conducted using the double stapling technique. Performing transanal specimen extraction using needlescopic forceps improves aesthetic outcomes and reduces post-operative pain and the risk of abdominal incisional hernias. This method is an easy to introduce a form of reduced-port surgery because of its feasibility and conventional port arrangement. Hence, we consider that it is an option for minimally invasive surgery.

Clinical pathway to discharge 3 days after colorectal endoscopic submucosal dissection.

BACKGROUND AND AIM: Colorectal endoscopic submucosal dissection (ESD) is a useful treatment method; however, no index has been established for time for patient to start food ingestion or be discharged after ESD. We investigated the potential of a clinical pathway in which patients started food ingestion on day 2 after ESD and were discharged on day 3. METHODS: A total of 382 patients underwent colorectal ESD between 2006 and 2012. A flow chart of a clinical pathway was prepared based on the data obtained, with the aim of shortening hospital stay after ESD. RESULTS: Mean duration of postoperative hospital stay in the 382 patients was 5.3 ± 1.8 days. The most common cause of extended hospital stay was abnormal blood test finding, as detected in 50 patients in group C (n = 131; 38.2%), followed by careful course observations, as noted in 48 patients in group C (n = 131; 36.6%). Regarding procedural accidents as a result of ESD, intraoperative perforation occurred in 15 patients (3.9%) and post-ESD bleeding in seven patients (1.8%), which extended the hospital stay. Food ingestion was started on day 2 when no abnormality was noted during ESD or in physical and imaging findings or blood tests on day 1. In the 86 patients who underwent the prepared clinical pathway as a validation study, 68 (79.0%) were discharged on day 3. Duration of postoperative hospital stay was 3.4 ± 1.2 days. CONCLUSION: Discharge may be possible 3 days after ESD when no abnormalities are noted during ESD or on post-ESD day 1.

[A case of cecum colon cancer with lymph node metastasis successfully treated with XELOX plus bevacizumab].

A 65-year-old woman with a history of constipation presented at our hospital and was subsequently diagnosed with advanced cecum cancer. We performed laparoscopic right hemicolectomy in January 2009, with pathological findings reveal- ing the presence of Stage III b (pT3, pN3, cM0, Cur A) disease. The patient was treated with a uracil/tegafur plus Leucovorin (UFT/LV) adjuvant chemotherapy regimen for six months. In June 2010, bold examination indicated an elevated level of tumor marker CA19-9. Computed tomography (CT) and positron emission tomography (PET)/CT revealed Virchow's and para-aortic lymph node metastasis. Therapy with XELOX and bevacizumab (Bmab) was administered and continued for 10 cycles. Capecitabine+Bmab treatment was also administered for 11 courses due to an adverse event of peripheral neuropathy. Follow-up revealed both the Virchow's and para-aortic lymph node metastasis had disappeared upon completion of treatment. In November, 2011 the patient was considered to have achieved a clinical complete response (CR) and continues to be followed with no further disease progression.

Recurrent Ipsilateral C5 Nerve Palsy Associated With Hereditary Neuropathy With Liability to Pressure Palsy.

Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant disorder caused by heteroplasmic deletion of the peripheral myelin protein 22 (PMP22) gene. HNPP typically presents with clinical features such as peroneal nerve palsy or cubital tunnel syndrome, which are caused by mechanical compression. Diagnosing cases where neuropathy is absent at the pressure site can be challenging. This is a case study of an 18-year-old man who underwent surgery on the left side of his neck over 10 years ago to remove lymphadenopathy. Following the surgery, he experienced recurrent weakness but only sought medical attention when muscle weakness persisted for longer than a week postoperatively. Upon admission, the patient exhibited neurological symptoms consistent with C5 neuropathy, mainly affecting the deltoid muscles. No serological abnormalities were found to be associated with neuropathy. Neither magnetic resonance imaging nor computed tomography scans detected any lesions around the C5 nerve root. The posture during sleep was believed to cause excessive extension of the C5 nerve root, leading to the assumption that there was some vulnerability in the nerve. A transient sensory loss in the area innervated by the ulnar nerve prompted us to examine the fluorescence in situ hybridization study on the blood sample, which revealed a deletion of the PMP22 gene. The patient was diagnosed with HNPP and was advised to avoid risky postures. Following the implementation of these lifestyle changes, he did not experience any further weakness in his shoulders.

Alpha-synuclein promotes PRMT5-mediated H4R3me2s histone methylation by interacting with the BAF complex.

α-Synuclein (αS) is a key molecule in the pathomechanism of Parkinson's disease. Most studies on αS to date have focused on its function in the neuronal cytosol, but its action in the nucleus has also been postulated. Indeed, several lines of evidence indicate that overexpressed αS leads to epigenomic alterations. To clarify the functional role of αS in the nucleus and its pathological significance, HEK293 cells constitutively expressing αS were used to screen for nuclear proteins that interact with αS by nanoscale liquid chromatography/tandem mass spectrometry. Interactome analysis of the 229 identified nuclear proteins revealed that αS interacts with the BRG1-associated factor (BAF) complex, a family of multi-subunit chromatin remodelers important for neurodevelopment, and protein arginine methyltransferase 5 (PRMT5). Subsequent transcriptomic analysis also suggested a functional link between αS and the BAF complex. Based on these results, we analyzed the effect of αS overexpression on the BAF complex in neuronally differentiated SH-SY5Y cells and found that induction of αS disturbed the BAF maturation process, leading to a global increase in symmetric demethylation of histone H4 on arginine 3 (H4R3me2s) via enhanced BAF-PRMT5 interaction. Chromatin immunoprecipitation sequencing confirmed accumulated H4R3me2s methylation near the transcription start site of the neuronal cell adhesion molecule (NRCAM) gene, which has roles during neuronal differentiation. Transcriptional analyses confirmed the negative regulation of NRCAM by αS and PRMT5, which was reconfirmed by multiple datasets in the Gene Expression Omnibus (GEO) database. Taken together, these findings suggest that the enhanced binding of αS to the BAF complex and PRMT5 may cooperatively affect the neuronal differentiation process.

Dysregulation of SNX1-retromer axis in pharmacogenetic models of Parkinson's disease.

Since the identification of vacuolar protein sorting (VPS) 35, as a causative molecule for familial Parkinson's disease (PD), retromer-mediated endosomal machinery has been a rising factor in the pathogenesis of the disease. The retromer complex cooperates with sorting nexin (SNX) dimer and DNAJC13, another causal molecule in PD, to transport cargoes from endosomes to the trans-Golgi network, and is also involved in mitochondrial dynamics and autophagy. Retromer dysfunction may induce neuronal death leading to PD via several biological cascades, including misfolded, insoluble α-synuclein (aS) accumulation and mitochondrial dysfunction; however, the detailed mechanisms remain poorly understood. In this study, we showed that the stagnation of retromer-mediated retrograde transport consistently occurs in different PD-mimetic conditions, i.e., overexpression of PD-linked mutant DNAJC13, excess aS induction, or toxin-induced mitochondrial dysfunction. Mechanistically, DNAJC13 was found to be involved in clathrin-dependent retromer transport as a functional modulator of SNX1 together with heat shock cognate 70 kDa protein (Hsc70), which was controlled by the binding and dissociation of DNAJC13 and SNX1 in an Hsc70 activity-dependent manner. In addition, excess amount of aS decreased the interaction between SNX1 and VPS35, the core component of retromer. Furthermore, R33, a pharmacological retromer chaperone, reduced insoluble aS and mitigated rotenone-induced neuronal apoptosis. These findings suggest that retrograde transport regulated by SNX1-retromer may be profoundly involved in the pathogenesis of PD and is a potential target for disease-modifying therapy for the disease.