Glycemic Control and Coronary Stent Failure in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: The impact of glycemic control in the risk of stent failure in subjects with type 2 diabetes (T2D) is currently unknown. OBJECTIVES: This study sought to study whether poor glycemic control is associated with a higher risk of stent failure in subjects with T2D. METHODS: This observational study included all patients in Sweden with T2D who underwent implantation of second-generation drug-eluting stents (DES) during 2010 to 2020. The exposure variable was the updated mean of glycated hemoglobin (HbA1c). Individuals were stratified by glycemic control, with HbA1c 6.1% to 7.0% (43-53 mmol/mol) as the reference group. The primary endpoint was the occurrence of stent failure (in-stent restenosis and stent thrombosis). The main result was analyzed in a complete cases model. Sensitivity analyses were performed for missing data and a model with death as a competing risk. RESULTS: The study population consisted of 52,457 individuals (70,453 DES). The number of complete cases was 24,411 (29,029 DES). The median follow-up was 6.4 years. The fully adjusted HR was 1.10 (95% CI: 0.80-1.52) for HbA1c of ≤5.5% (≤37 mmol/mol), 1.02 (95% CI: 0.85-1.23) for HbA1c of 5.6% to 6.0% (38-42 mmol/mol), 1.25 (95% CI: 1.11-1.41) for HbA1c of 7.1% to 8.0% (54-64 mmol/mol), 1.30 (95% CI: 1.13-1.51) for HbA1c of 8.1% to 9.0% (65-75 mmol/mol), 1.46 (95% CI: 1.21-1.76) for HbA1c of 9.1% to 10.0% (76-86 mmol/mol), and 1.33 (95% CI: 1.06-1.66) for HbA1c of ≥10.1% (≥87 mmol/mol). Sensitivity analyses did not change the main result. CONCLUSIONS: We found a significant association between poor glycemic control and a higher risk of stent failure driven by in-stent restenosis.

Trends in Survival After First Myocardial Infarction in People With Diabetes.

BACKGROUND: The aim of this study was to investigate temporal trends in survival and subsequent cardiovascular events in a nationwide myocardial infarction population with and without diabetes. METHODS AND RESULTS: Between 2006 and 2020, we identified 2527 individuals with type 1 diabetes, 48 321 individuals with type 2 diabetes and 243 170 individuals without diabetes with first myocardial infarction in national health care registries. Outcomes were trends in all-cause death after 30 and 365 days, cardiovascular death and major adverse cardiovascular events (ie, nonfatal stroke, nonfatal myocardial infarction, cardiovascular death, and heart failure hospitalization). Pseudo-observations were used to estimate the mortality risk, with 95% CIs, using linear regression, adjusted for age and sex. Individuals with type 1 diabetes were younger (62±12.2 years) and more often women (43.6%) compared with individuals with type 2 diabetes (75±10.8 years; women, 38.1%), and individuals without diabetes (73±13.2 years; women, 38.4%). Early death decreased in people without diabetes from 23.1% to 17.5%, (annual change -0.48% [95% CI, -0.52% to -0.44%]) and in people with type 2 diabetes from 22.6% to 19.3% (annual change, -0.33% [95% CI, -0.43% to -0.24%]), with no such significant trend in people with type 1 diabetes from 23.8% to 21.7% (annual change, -0.18% [95% CI, -0.53% to 0.17%]). Similar trends were observed with regard to 1-year death, cardiovascular death, and major adverse cardiovascular events. CONCLUSIONS: During the past 15 years, the trend in survival and major adverse cardiovascular events in people with first myocardial infarction without diabetes and with type 2 diabetes have improved significantly. In contrast, a similar improvement was not seen in people with type 1 diabetes.

Discordance between mean glucose and time in range in relation to HbA1c in individuals with type 1 diabetes: results from the GOLD and SILVER trials.

AIMS/HYPOTHESIS: Previous studies have shown that individuals with similar mean glucose levels (MG) or percentage of time in range (TIR) may have different HbA1c values. The aim of this study was to further elucidate how MG and TIR are associated with HbA1c. METHODS: Data from the randomised clinical GOLD trial (n=144) and the follow-up SILVER trial (n=98) of adults with type 1 diabetes followed for 2.5 years were analysed. A total of 596 paired HbA1c/continuous glucose monitoring measurements were included. Linear mixed-effects models were used to account for intra-individual correlations in repeated-measures data. RESULTS: In the GOLD trial, the mean age of the participants (± SD) was 44±13 years, 63 (44%) were female, and the mean HbA1c (± SD) was 72±9.8 mmol/mol (8.7±0.9%). When correlating MG with HbA1c, MG explained 63% of the variation in HbA1c (r=0.79, p<0.001). The variation in HbA1c explained by MG increased to 88% (r=0.94, p value for improvement of fit <0.001) when accounting for person-to-person variation in the MG-HbA1c relationship. Time below range (TBR; <3.9 mmol/l), time above range (TAR) level 2 (>13.9 mmol/l) and glycaemic variability had little or no effect on the association. For a given MG and TIR, the HbA1c of 10% of individuals deviated by >8 mmol/mol (0.8%) from their estimated HbA1c based on the overall association between MG and TIR with HbA1c. TBR and TAR level 2 significantly influenced the association between TIR and HbA1c. At a given TIR, each 1% increase in TBR was related to a 0.6 mmol/mol lower HbA1c (95% CI 0.4, 0.9; p<0.001), and each 2% increase in TAR level 2 was related to a 0.4 mmol/mol higher HbA1c (95% CI 0.1, 0.6; p=0.003). However, neither TIR, TBR nor TAR level 2 were significantly associated with HbA1c when accounting for MG. CONCLUSIONS/INTERPRETATION: Inter-individual variations exist between MG and HbA1c, as well as between TIR and HbA1c, with clinically important deviations in relatively large groups of individuals with type 1 diabetes. These results may provide important information to both healthcare providers and individuals with diabetes in terms of prognosis and when making diabetes management decisions.

The SGLT2 inhibitor Empagliflozin promotes post-stroke functional recovery in diabetic mice.

Type-2 diabetes (T2D) worsens stroke recovery, amplifying post-stroke disabilities. Currently, there are no therapies targeting this important clinical problem. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are potent anti-diabetic drugs that also efficiently reduce cardiovascular death and heart failure. In addition, SGLT2i facilitate several processes implicated in stroke recovery. However, the potential efficacy of SGLT2i to improve stroke recovery in T2D has not been investigated. Therefore, we determined whether a post-stroke intervention with the SGLT2i Empagliflozin could improve stroke recovery in T2D mice. T2D was induced in C57BL6J mice by 8 months of high-fat diet feeding. Hereafter, animals were subjected to transient middle cerebral artery occlusion and treated with vehicle or the SGLTi Empagliflozin (10 mg/kg/day) starting from 3 days after stroke. A similar study in non diabetic mice was also conducted. Stroke recovery was assessed using the forepaw grip strength test. To identify potential mechanisms involved in the Empagliflozin-mediated effects, several metabolic parameters were assessed. Additionally, neuronal survival, neuroinflammation, neurogenesis and cerebral vascularization were analyzed using immunohistochemistry/quantitative microscopy. Empagliflozin significantly improved stroke recovery in T2D but not in non-diabetic mice. Improvement of functional recovery was associated with lowered glycemia, increased serum levels of fibroblast growth factor-21 (FGF-21), and the normalization of T2D-induced aberration of parenchymal pericyte density. The global T2D-epidemic and the fact that T2D is a major risk factor for stroke are drastically increasing the number of people in need of efficacious therapies to improve stroke recovery. Our data provide a strong incentive for the potential use of SGLT2i for the treatment of post-stroke sequelae in T2D.

Nuclear Hsp104 safeguards the dormant translation machinery during quiescence.

The resilience of cellular proteostasis declines with age, which drives protein aggregation and compromises viability. The nucleus has emerged as a key quality control compartment that handles misfolded proteins produced by the cytosolic protein biosynthesis system. Here, we find that age-associated metabolic cues target the yeast protein disaggregase Hsp104 to the nucleus to maintain a functional nuclear proteome during quiescence. The switch to respiratory metabolism and the accompanying decrease in translation rates direct cytosolic Hsp104 to the nucleus to interact with latent translation initiation factor eIF2 and to suppress protein aggregation. Hindering Hsp104 from entering the nucleus in quiescent cells results in delayed re-entry into the cell cycle due to compromised resumption of protein synthesis. In sum, we report that cytosolic-nuclear partitioning of the Hsp104 disaggregase is a critical mechanism to protect the latent protein synthesis machinery during quiescence in yeast, ensuring the rapid restart of translation once nutrients are replenished.

Effects of exenatide on coronary stent's endothelialization in subjects with type 2 diabetes: a randomized controlled trial. The Rebuild study.

BACKGROUND: Subjects with type 2 diabetes (T2D) have a higher risk of in-stent restenosis and stent thrombosis. The activation of the glucagon-like peptide-1 receptor (GLP-1R) has been suggested to induce several effects on the vasculature that may reduce the risk of stent failure following an angioplasty. The aim of this study is to evaluate the effect of the GLP-1R agonist exenatide on endothelialization of a modern drug-eluting stent (DES) in subjects with T2D. METHODS: 38 subjects with T2D who were eligible for revascularization with implantation of DES were randomized to treatment with exenatide (once weekly) plus standard treatment, or to standard treatment alone. After 12 weeks, a new coronary angiography was performed to evaluate the percentage of strut coverage (primary endpoint) and the presence of neo-atherosclerosis by optical coherence tomography. This study was approved by the Stockholm's Ethical Review Board. RESULTS: The two groups were well balanced regarding baseline clinical characteristics. Strut coverage was 95% (88.7-98.5%) in the exenatide group and 91.4% (88.8-98.5%) in the control group (p = 0.692). There were no significant differences between groups neither in the thickness of neo-intima (0.2 mm in both groups, p = 0.471), nor the maximal in-stent obstruction by neo-intima (15.5% in exenatide group vs 14.7% in control group, p = 0.801). No significant differences were detected in the rate of target lesion revascularization between groups (p = 0.224). CONCLUSION: Twelve weeks treatment with exenatide did not lead to a significantly better stent coverage in people with T2D. No significant differences in the occurrence of neo-atherosclerosis were detected between groups. TRIAL REGISTRATION: The study was registered at www. CLINICALTRIALS: gov (Rebuild Study, NCT02621489).

Correlations between insulin-degrading enzyme and metabolic markers in patients diagnosed with type 2 diabetes, Alzheimer's disease, and healthy controls: a comparative study.

PURPOSE: This study aimed to explore correlations between insulin-degrading enzyme (IDE) and markers of metabolic function in a group of patients diagnosed with type 2 diabetes mellitus (T2DM) or Alzheimer's disease (AD) and metabolically healthy volunteers. METHOD: We included 120 individuals (47 with T2DM, 9 with AD, and 64 healthy controls). Serum levels of IDE were measured with commercial kits for ELISA. Differences in IDE levels between groups were analyzed with non-parametric ANCOVA, and correlations were analyzed with Spearman's rank correlations. We also investigated the influence of age, sex, and the use of insulin on the correlation using a non-parametric version of partial correlation. RESULTS: Patients diagnosed with T2DM had higher IDE levels than patients diagnosed with AD and healthy controls after adjustment for age and sex. IDE was increasingly associated with body mass index (BMI), fasting blood glucose, C-peptide, hemoglobin A1c (HbA1c), insulin resistance, and triglycerides. In stratified analyses, we found a decreasing partial correlation between IDE and HbA1c in patients diagnosed with AD and a decreasing partial correlation between IDE and C-peptide in healthy controls. In patients diagnosed with T2DM, we found no partial correlations. CONCLUSION: These results indicate that IDE is essential in metabolic function and might reflect metabolic status, although it is not yet a biomarker that can be utilized in clinical practice. Further research on IDE in human blood may provide crucial insights into the full function of the enzyme.

Calmodulin regulates protease versus co-chaperone activity of a metacaspase.

Metacaspases are ancestral homologs of caspases that can either promote cell death or confer cytoprotection. Furthermore, yeast (Saccharomyces cerevisiae) metacaspase Mca1 possesses dual biochemical activity: proteolytic activity causing cell death and cytoprotective, co-chaperone-like activity retarding replicative aging. The molecular mechanism favoring one activity of Mca1 over another remains elusive. Here, we show that this mechanism involves calmodulin binding to the N-terminal pro-domain of Mca1, which prevents its proteolytic activation and promotes co-chaperone-like activity, thus switching from pro-cell death to anti-aging function. The longevity-promoting effect of Mca1 requires the Hsp40 co-chaperone Sis1, which is necessary for Mca1 recruitment to protein aggregates and their clearance. In contrast, proteolytically active Mca1 cleaves Sis1 both in vitro and in vivo, further clarifying molecular mechanism behind a dual role of Mca1 as a cell-death protease versus gerontogene.

Time-trends in body mass index, and overweight and obesity as independent risk factors for diabetes angiopathy in young females with type 1 diabetes - A nationwide study in Sweden.

AIMS: To examine time-trends in BMI-distributions of young females with and without type 1 diabetes (T1D), with focus on the upper half of the distribution i.e., the median and above, and to explore if overweight and obesity independently increase risk of diabetes angiopathy. METHODS: Population-based cohort study of 3,473 females with T1D, 16-35 years, identified in the Swedish National Diabetes Registers, January 2005 to October 2015, and 8,487 females from the background population. BMI-distributions were examined using kernel density estimates and quantile regression. Hazard ratios (HRs) and 95 % confidence intervals (CIs) for angiopathy in overweight/obese subjects were estimated with adjusted Cox regression. RESULTS: The BMI-distribution in females with T1D was right shifted to that of the background population (p < 0.001). The 90th percentile and median BMI increased equally overtime in both groups, but females with T1D started from a higher baseline. In T1D, HRs were significantly increased for any angiopathy in individuals with obesity (adj HR 1.37 (CI 1.14-1.64)), and for retinopathy; adj HRs (CIs): overweight; 1.15 (1.02-1.29), obesity; 1.30 (1.08-1.56). CONCLUSIONS: Females with T1D have increasing BMI overtime and are heavier than females without T1D. Overweight and obesity are by themselves risk factors for angiopathy.

Calcineurin stimulation by Cnb1p overproduction mitigates protein aggregation and α-synuclein toxicity in a yeast model of synucleinopathy.

The calcium-responsive phosphatase, calcineurin, senses changes in Ca2+ concentrations in a calmodulin-dependent manner. Here we report that under non-stress conditions, inactivation of calcineurin signaling or deleting the calcineurin-dependent transcription factor CRZ1 triggered the formation of chaperone Hsp100p (Hsp104p)-associated protein aggregates in Saccharomyces cerevisiae. Furthermore, calcineurin inactivation aggravated α-Synuclein-related cytotoxicity. Conversely, elevated production of the calcineurin activator, Cnb1p, suppressed protein aggregation and cytotoxicity associated with the familial Parkinson's disease-related mutant α-Synuclein A53T in a partly CRZ1-dependent manner. Activation of calcineurin boosted normal localization of both wild type and mutant α-synuclein to the plasma membrane, an intervention previously shown to mitigate α-synuclein toxicity in Parkinson's disease models. The findings demonstrate that calcineurin signaling, and Ca2+ influx to the vacuole, limit protein quality control in non-stressed cells and may have implications for elucidating to which extent aberrant calcineurin signaling contributes to the progression of Parkinson's disease(s) and other synucleinopathies. Video Abstract.

All-Cause Mortality and Cardiovascular and Microvascular Diseases in Latent Autoimmune Diabetes in Adults.

OBJECTIVE: Latent autoimmune diabetes in adults (LADA) is a heterogenous, slowly progressing autoimmune diabetes. We aim to contribute new knowledge on the long-term prognosis of LADA with varying degrees of autoimmunity by comparing it to type 2 diabetes and adult-onset type 1 diabetes. RESEARCH DESIGN AND METHODS: This Swedish population-based study included newly diagnosed LADA (n = 550, stratified into LADAlow and LADAhigh by median autoimmunity level), type 2 diabetes (n = 2,001), adult-onset type 1 diabetes (n = 1,573), and control subjects without diabetes (n = 2,355) in 2007-2019. Register linkages provided information on all-cause mortality, cardiovascular diseases (CVDs), diabetic retinopathy, nephropathy, and clinical characteristics during follow-up. RESULTS: Mortality was higher in LADA (hazard ratio [HR] 1.44; 95% CI 1.03, 2.02), type 1 (2.31 [1.75, 3.05]), and type 2 diabetes (1.31 [1.03, 1.67]) than in control subjects. CVD incidence was elevated in LADAhigh (HR 1.67; 95% CI 1.04, 2.69) and type 2 diabetes (1.53 [1.17, 2.00]), but not in LADAlow or type 1 diabetes. Incidence of retinopathy but not nephropathy was higher in LADA (HR 2.25; 95% CI 1.64, 3.09), including LADAhigh and LADAlow than in type 2 diabetes (unavailable in type 1 diabetes). More favorable blood pressure and lipid profiles, but higher HbA1c levels, were seen in LADA than type 2 diabetes at baseline and throughout follow-up, especially in LADAhigh, which resembled type 1 diabetes in this respect. CONCLUSIONS: Despite having fewer metabolic risk factors than type 2 diabetes, LADA has equal to higher risks of death, CVD, and retinopathy. Poorer glycemic control, particularly in LADAhigh, highlights the need for improved LADA management.

Empagliflozin is associated with lower cardiovascular risk compared with dipeptidyl peptidase-4 inhibitors in adults with and without cardiovascular disease: EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study results from Europe and Asia.

BACKGROUND: Studies that have reported lower risk for cardiovascular outcomes in users of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) are limited by residual cofounding and lack of information on prior cardiovascular disease (CVD). This study compared risk of cardiovascular events in patients within routine care settings in Europe and Asia with type 2 diabetes (T2D) initiating empagliflozin compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) stratified by pre-existing CVD and history of heart failure (HF). METHODS AND RESULTS: Adults initiating empagliflozin and DPP-4i in 2014-2018/19 from 11 countries in Europe and Asia were compared using propensity score matching and Cox proportional hazards regression to assess differences in rates of primary outcomes: hospitalisation for heart failure (HHF), myocardial infarction (MI), stroke; and secondary outcomes: cardiovascular mortality (CVM), coronary revascularisation procedure, composite outcome including HHF or CVM, and 3-point major adverse cardiovascular events (MACE: MI, stroke and CVM). Country-specific results were meta-analysed and pooled hazard ratios (HR) with 95% confidence intervals (CI) from random-effects models are presented. In total, 85,244 empagliflozin/DPP4i PS-matched patient pairs were included with overall mean follow-up of 0.7 years. Among those with pre-existing CVD, lower risk was observed for HHF (HR 0.74; 95% CI 0.64-0.86), CVM (HR 0.55; 95% CI 0.38-0.80), HHF or CVM (HR 0.57; 95% CI 0.48-0.67) and stroke (HR 0.79; 95% CI 0.67-0.94) in patients initiating empagliflozin vs DPP-4i. Similar patterns were observed among patients without pre-existing CVD and those with and without pre-existing HF. CONCLUSION: These results from diverse patient populations in routine care settings across Europe and Asia demonstrate that initiation of empagliflozin compared to DPP-4i results in favourable cardioprotective effects regardless of pre-existing CVD or HF status.

The yeast guanine nucleotide exchange factor Sec7 is a bottleneck in spatial protein quality control and detoxifies neurological disease proteins.

ER-to-Golgi trafficking partakes in the sorting of misfolded cytoplasmic proteins to reduce their cytological toxicity. We show here that yeast Sec7, a protein involved in proliferation of the Golgi, is part of this pathway and participates in an Hsp70-dependent formation of insoluble protein deposits (IPOD). Sec7 associates with the disaggregase Hsp104 during a mild heat shock and increases the rate of Hsp104 diffusion in an Hsp70-dependent manner when overproduced. Sec7 overproduction increased formation of IPODs from smaller aggregates and mitigated the toxicity of Huntingtin exon-1 upon heat stress while Sec7 depletion increased sensitivity to aẞ42 of the Alzheimer's disease and α-synuclein of the Parkinson's disease, suggesting a role of Sec7 in mitigating proteotoxicity.

Arabidopsis metacaspase MC1 localizes in stress granules, clears protein aggregates, and delays senescence.

Stress granules (SGs) are highly conserved cytoplasmic condensates that assemble in response to stress and contribute to maintaining protein homeostasis. These membraneless organelles are dynamic, disassembling once the stress is no longer present. Persistence of SGs due to mutations or chronic stress has been often related to age-dependent protein-misfolding diseases in animals. Here, we find that the metacaspase MC1 is dynamically recruited into SGs upon proteotoxic stress in Arabidopsis (Arabidopsis thaliana). Two predicted disordered regions, the prodomain and the 360 loop, mediate MC1 recruitment to and release from SGs. Importantly, we show that MC1 has the capacity to clear toxic protein aggregates in vivo and in vitro, acting as a disaggregase. Finally, we demonstrate that overexpressing MC1 delays senescence and this phenotype is dependent on the presence of the 360 loop and an intact catalytic domain. Together, our data indicate that MC1 regulates senescence through its recruitment into SGs and this function could potentially be linked to its remarkable protein aggregate-clearing activity.

Treatment Satisfaction and Well-Being With CGM in People With T1D: An Analysis Based on the GOLD Randomized Trial.

BACKGROUND: The GOLD trial demonstrated that continuous glucose monitoring (CGM) in people with type 1 diabetes (T1D) managed with multiple daily insulin injections (MDI) improved not only glucose control but also overall well-being and treatment satisfaction. This analysis investigated which factors contributed to improved well-being and treatment satisfaction with CGM. METHODS: The GOLD trial was a randomized crossover trial comparing CGM versus self-monitored blood glucose (SMBG) over 16 months. Endpoints included well-being measured by the World Health Organization-Five Well-Being Index (WHO-5) and treatment satisfaction by the Diabetes Treatment Satisfaction Questionnaire (DTSQ) as well as glucose metrics. Multivariable R2-decomposition was used to understand which variables contributed most to treatment satisfaction. RESULTS: A total of 139 participants were included. Multivariable analyses revealed that increased convenience and flexibility contributed to 60% (95% confidence interval [CI] = 50%-69%) of the improvement in treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire change version [DTSQc]) observed with CGM, whereas perceived effects on hypoglycemia and hyperglycemia only contributed to 6% (95% CI = 2%-11%) of improvements. Significant improvements in well-being (WHO-5) by CGM were observed for the following: feeling cheerful (P = .025), calm and relaxed (P = .024), being active (P = .046), and waking up fresh and rested (P = .044). HbA1c reductions and increased time in range (TIR) were associated with increased treatment satisfaction, whereas glycemic variability was not. HbA1c reduction showed also an association with increased well-being and increased TIR with less diabetes-related distress. CONCLUSIONS: While CGM improves glucose control in people with T1D on MDI, increased convenience and flexibility through CGM is of even greater importance for treatment satisfaction and patient well-being. These CGM-mediated effects should be taken into account when considering CGM initiation.

Correlation between insulin-degrading enzyme versus total tau and selected cytokines in patients with Alzheimer´s disease compared to non-demented controls.

OBJECTIVE: It has been increasingly recognized that the pathological progress of Alzheimer´s disease (AD) is connected to metabolic function and inflammation. Insulin-degrading enzyme (IDE) is essential for glucose metabolism and the degradation of amyloid-ß. We aimed to explore the associations between IDE, total tau, and cytokines levels in plasma from subjects with AD and non-demented controls. METHODS AND MATERIAL: Plasma samples (18 patients diagnosed with AD and 6 non-demented controls) from the Netherlands Brain Bank were used to analyze IDE levels and total tau with an enzyme-linked immunosorbent assay. Cytokines were analyzed with Luminex custom plex assays for interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-α). Results were analyzed using the Mann-Whitney U and Spearman´s rank correlation tests. RESULTS: Total tau in plasma was significantly increased in AD subjects compared to non-demented control subjects (p = 0.044). Total tau was positively correlated with IDE levels in plasma in all subjects (r = 0.494, p = 0.017). Significant correlations could be demonstrated between plasma levels of IDE and IL-6 (r = 0.546, p = 0.019), IL-8 (r = 0.664, p = 0.003), IL-10 (r = 0.833, p < 0.001), and TNF-α (r = 0.633, p = 0.005) in subjects with AD, but not in non-demented controls. CONCLUSION: Results from this study suggest that plasma IDE levels may be associated with inflammation and neurodegeneration and could potentially be a target for future diagnostic and treatment strategies.

Syntaxin 5-dependent phosphorylation of the small heat shock protein Hsp42 and its role in protein quality control.

The small heat shock protein Hsp42 and the t-SNARE protein Sed5 have central roles in the sequestration of misfolded proteins into insoluble protein deposits in the yeast Saccharomyces cerevisiae. However, whether these proteins/processes interact in protein quality control (PQC) is not known. Here, we show that Sed5 and anterograde trafficking modulate phosphorylation of Hsp42 partially via the MAPK kinase Hog1. Such phosphorylation, specifically at residue S215, abrogated the co-localization of Hsp42 with the Hsp104 disaggregase, aggregate clearance, chaperone activity, and sequestration of aggregates to IPOD and mitochondria. Furthermore, we found that Hsp42 is hyperphosphorylated in old cells leading to a drastic failure in disaggregation. Old cells also displayed a retarded anterograde trafficking, which, together with slow aggregate clearance and hyperphosphorylation of Hsp42, could be counteracted by Sed5 overproduction. We hypothesize that the breakdown of proper PQC during yeast aging may, in part, be due to a retarded anterograde trafficking leading to hyperphosphorylation of Hsp42.