Localization of PPM1H phosphatase tunes Parkinson's disease-linked LRRK2 kinase-mediated Rab GTPase phosphorylation and ciliogenesis.

PPM1H phosphatase reverses Parkinson's disease-associated, Leucine Rich Repeat Kinase 2-mediated Rab GTPase phosphorylation. We show here that PPM1H relies on an N-terminal amphipathic helix for Golgi localization. The amphipathic helix enables PPM1H to bind to liposomes in vitro, and small, highly curved liposomes stimulate PPM1H activity. We artificially anchored PPM1H to the Golgi, mitochondria, or mother centriole. Our data show that regulation of Rab10 GTPase phosphorylation requires PPM1H access to Rab10 at or near the mother centriole. Moreover, poor colocalization of Rab12 explains in part why it is a poor substrate for PPM1H in cells but not in vitro. These data support a model in which localization drives PPM1H substrate selection and centriolar PPM1H is critical for regulation of Rab GTPase-regulated ciliogenesis. Moreover, Golgi localized PPM1H may maintain active Rab GTPases on the Golgi to carry out their nonciliogenesis-related functions in membrane trafficking.

Enzymatic analysis of WWP2 E3 ubiquitin ligase using protein microarrays identifies autophagy-related substrates.

WWP2 is a HECT E3 ligase that targets protein Lys residues for ubiquitination and is comprised of an N-terminal C2 domain, four central WW domains, and a C-terminal catalytic HECT domain. The peptide segment between the middle WW domains, the 2,3-linker, is known to autoinhibit the catalytic domain, and this autoinhibition can be relieved by phosphorylation at Tyr369. Several protein substrates of WWP2 have been identified, including the tumor suppressor lipid phosphatase PTEN, but the full substrate landscape and biological functions of WWP2 remain to be elucidated. Here, we used protein microarray technology and the activated enzyme phosphomimetic mutant WWP2Y369E to identify potential WWP2 substrates. We identified 31 substrate hits for WWP2Y369E using protein microarrays, of which three were known autophagy receptors (NDP52, OPTN, and SQSTM1). These three hits were validated with in vitro and cell-based transfection assays and the Lys ubiquitination sites on these proteins were mapped by mass spectrometry. Among the mapped ubiquitin sites on these autophagy receptors, many had been previously identified in the endogenous proteins. Finally, we observed that WWP2 KO SH-SH5Y neuroblastoma cells using CRISPR-Cas9 showed a defect in mitophagy, which could be rescued by WWP2Y369E transfection. These studies suggest that WWP2-mediated ubiquitination of the autophagy receptors NDP52, OPTN, and SQSTM1 may positively contribute to the regulation of autophagy.

Comparative analysis of the catalytic regulation of NEDD4-1 and WWP2 ubiquitin ligases.

NEDD4-1 E3 ubiquitin protein ligase (NEDD4-1) and WW domain-containing E3 ubiquitin ligase (WWP2) are HECT family ubiquitin E3 ligases. They catalyze Lys ubiquitination of themselves and other proteins and are important in cell growth and differentiation. Regulation of NEDD4-1 and WWP2 catalytic activities is important for controlling cellular protein homeostasis, and their dysregulation may lead to cancer and other diseases. Previous work has implicated noncatalytic regions, including the C2 domain and/or WW domain linkers in NEDD4-1 and WWP2, in contributing to autoinhibition of the catalytic HECT domains by intramolecular interactions. Here, we explored the molecular mechanisms of these NEDD4-1 and WWP2 regulatory regions and their interplay with allosteric binding proteins such as Nedd4 family-interacting protein (NDFIP1), engineered ubiquitin variants, and linker phosphomimics. We found that in addition to influencing catalytic activities, the WW domain linker regions in NEDD4-1 and WWP2 can impact product distribution, including the degree of polyubiquitination and Lys-48 versus Lys-63 linkages. We show that allosteric activation by NDFIP1 or engineered ubiquitin variants is largely mediated by relief of WW domain linker autoinhibition. WWP2-mediated ubiquitination of WW domain-binding protein 2 (WBP2), phosphatase and tensin homolog (PTEN), and p62 proteins by WWP2 suggests that substrate ubiquitination can also be influenced by WW linker autoinhibition, although to differing extents. Overall, our results provide a deeper understanding of the intricate and multifaceted set of regulatory mechanisms in the control of NEDD4-1-related ubiquitin ligases.

Effect of the WeCareAdvisor™ on family caregiver outcomes in dementia: a pilot randomized controlled trial.

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are universal and associated with multiple negative outcomes. This pilot randomized controlled trial (RCT) evaluated the effect of using the WeCareAdvisor, an innovative web-based tool developed to enable family caregivers to assess, manage, and track BPSD. METHODS: This RCT enrolled 57 dementia family caregivers from community and clinical settings in Ann Arbor, Michigan and Baltimore, Maryland. Participants were randomly assigned to immediate use of the WeCareAdvisor tool (WCA, n = 27) or a Waitlist control group (n = 30) that received the tool after a one-month waiting period. Outcomes for the caregiver and the person they were caring for were assessed at baseline (T0) and one-month followup for both the WCA (T1) and Waitlist control (T2) groups. RESULTS: Caregiver mean age was 65.9 ± 14.0 years old. About half (49%) were spouses. Baseline characteristics were comparable between groups except for mean caregiver confidence which was higher in the control group (WCA 35.0 ± 10.0 vs. Waitlist control 39.7 ± 6.9, p = 0.04). There were no significant differences between the WCA and control groups in characteristics of the person with dementia. After their one-month of tool use (T1), WCA caregivers showed significant within group improvement in caregiver distress (- 6.08 ± 6.31 points, t = - 4.82, p < 0.0001) and behavioral frequency (- 3.60 ± 5.05, t = - 3.56, p = 0.002), severity (- 3.24 ± 3.87, t = - 4.19, p = 0.0003) and total behavioral score (- 6.80 ± 10.73, t = - 3.17, p = 004). In the same timeframe, Waitlist control caregivers showed a significant decrease in confidence (- 6.40 ± 10.30, t = - 3.40, p = 0.002). The WCA group showed greater improvement in distress compared to the Waitlist group (T0-T1; t = - 2.49, p = 0.02), which remained significant after adjusting for site and baseline distress. There were no significant between-group differences in caregiver confidence or other secondary outcomes. After their one month of tool use (T2), the Waitlist group also showed significant improvement in caregiver distress (- 3.72 ± 7.53, t = - 2.66, p = 0.013), stress (- 0.41 ± 1.02, t = - 2.19, p = 0.037), confidence (4.38 ± 5.17, t = 4.56, p < 0.0001), burden (- 2.76 ± 7.26, t = - 2.05, p = 0.05), negative communication (- 1.48 ± 2.96, t = - 2.70, p = 0.012) and behavioral frequency (- 1.86 ± 4.58, t = - 2.19, p = 0.037); distress remained significant after adjustment. CONCLUSIONS: In this pilot RCT, WCA use resulted in a significant decrease in caregiver distress. Future research will identify whether longer use of WCA can impact other caregiver and behavioral outcomes. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02420535 (Date of registry: 4/20/2015, prior to the start of the clinical trial).

Antipsychotic Use and Physical Morbidity in Parkinson Disease.

OBJECTIVE: To determine if antipsychotic (AP) use in Parkinson disease (PD) patients is associated with increased physical morbidity. METHODS: Veterans Health Administration data (1999-2010) was used to examine physical morbidity risk associated with AP use in idiopathic PD patients with stable recent physical health. We compared 180-day morbidity rates in patients initiating an AP with matched non-AP users who survived for 180 days (matched on age, sex, race, index year, presence and duration of dementia, PD duration, delirium, hospitalization, Charlson Comorbidity Index, and new non-psychiatric medications; covarying for psychosis). Outcomes were 180-day emergency department (ED), and inpatient and outpatient visits. RESULTS: There were 6,679 matched PD pairs. Any AP use was associated with an increased risk of ED visit (HR: 1.64, 95% CI: 1.51, 1.77), inpatient care (HR: 1.58, 95% CI: 1.46, 1.71), and outpatient visits (IRR: 1.08, 95% CI: 1.05, 1.12). The risk was significantly higher for atypical AP use compared with nonuse for all three morbidity outcomes, and was similar for atypical and typical AP use. CONCLUSIONS: Any AP use, and atypical AP use, are associated with significantly increased physical morbidity risk in PD patients, as evidenced by increased ED, inpatient, and outpatient visits. These findings, which require replication, extend the risk associated with use of APs in this population from mortality to a broader range of adverse outcomes, and further highlight the need to use APs cautiously in PD patients.

Unintended Consequences of Adjusting Citalopram Prescriptions Following the 2011 FDA Warning.

OBJECTIVES: In 2011, the U.S. Food and Drug Administration (FDA) issued a safety announcement cautioning providers against prescribing citalopram above 40 mg per day given concerns for QT prolongation. We assessed the impact of a health system quality improvement initiative to identify patients taking higher than the recommended dose of citalopram. DESIGN: Retrospective cohort study. SETTING: Nine primary care clinics within the University of Michigan from March 2012 to February 2013. PARTICIPANTS: Adult patients taking a higher-than-recommended dose of citalopram following the FDA warning in 2011 (N = 199). MEASUREMENTS: Frequency of EKG monitoring, clinical factors associated with patients whose citalopram dose or use was adjusted, and potential impact of these changes on overall health care utilization was assessed. RESULTS: In patients prescribed higher-than-recommended doses of citalopram and who received a note from a pharmacist regarding the FDA warnings, only 8.5% received electrocardiogram (EKG) monitoring. Patients who were converted to an alternative antidepressant from citalopram were more likely to receive subsequent new prescriptions for benzodiazepines and sedative hypnotics (χ2 = 7.9, p = 0.048). Patients who had any adjustments to their antidepressant medication had greater overall health care utilization (OR: 25.0; 95% CI: 5.7-109.6; p < 0.001) than patients remaining on the same dose of citalopram. CONCLUSIONS: Despite a targeted quality intervention to address the FDA warning regarding citalopram, the warning was associated with low levels of EKG monitoring, increased anxiolytic and sedative medication use, and higher healthcare utilization. This finding may represent destabilization of patients on previously therapeutic doses of their antidepressant and an unintended consequence of the FDA warning.

Management of older adults with dementia who present to emergency services with neuropsychiatric symptoms.

OBJECTIVE: Our aim is to evaluate if and how neuropsychiatric symptoms (NPS) of dementia influence the management and disposition of older adults who present to emergency care settings. METHODS: This is a retrospective cohort study that involved the medical and psychiatric emergency departments of a tertiary academic medical center. Participants included patients ≥65 years of age with dementia who presented between 1 February 2012 and 16 July 2014 (n = 347). Subjects with documented NPS (n = 78) were compared with a group of subjects without documented NPS (n = 78) randomly selected from the overall group with dementia. The groups with and without NPS were compared on demographic, clinical, management, and disposition characteristics. RESULTS: Patients with NPS were more likely to have additional diagnostic testing performed and receive psychotropic medications including benzodiazepines and antipsychotics. Significantly fewer patients with NPS (59.0%) returned to their original setting from the emergency department than patients without NPS (76.9%). Among patients with NPS, those who had a motor disturbance were more likely to receive psychotropic medications than patients who did not have a motor disturbance. Depression/dysphoria, anxiety, disinhibition, irritability/lability, and motor disturbance were all associated with transfer from medical to psychiatric emergency department. Patients with depression/dysphoria or anxiety were more likely to be psychiatrically hospitalized. CONCLUSIONS: There are significant differences in the management of dementia with and without NPS in the emergency room setting. Developing and implementing successful methods to manage NPS in the emergency department and outpatient setting could potentially lead to less emergent psychotropic administration and reduce hospitalizations. Copyright © 2016 John Wiley & Sons, Ltd.

With a little help from my friends?: racial and gender differences in the role of social support in later-life depression medication adherence.

BACKGROUND: Social support has been shown to be an important factor in improving depression symptom outcomes, yet less is known regarding its impact on antidepressant medication adherence. This study sought to evaluate the role of perceived social support on adherence to new antidepressant medication prescriptions in later-life depression. METHODS: Data from two prospective observational studies of participants ≥60 years old, diagnosed with depression, and recently prescribed a new antidepressant (N = 452). Perceived social support was measured using a subscale of the Duke Social Support Index and medication adherence was assessed using a validated self-report measure. RESULTS: At four-month follow up, 68% of patients reported that they were adherent to antidepressant medication. Examining the overall sample, logistic regression analysis demonstrated no significant relationship between perceived social support and medication adherence. However, when stratifying the sample by social support, race, and gender, adherence significantly differed by race and gender in those with inadequate social support: Among those with low social support, African-American females were significantly less likely to adhere to depression treatment than white females (OR = 4.82, 95% CI = 1.14-20.28, p = 0.032) and white males (OR = 3.50, 95% CI = 1.03-11.92, p = 0.045). CONCLUSIONS: There is a significant difference in antidepressant medication adherence by race and gender in those with inadequate social support. Tailored treatment interventions for low social support should be sensitive to racial and gender differences.

The Association Between Benzodiazepine Use and Depression Outcomes in Older Veterans.

Benzodiazepines (BZDs) are commonly prescribed to older adults with depression, but it is unknown whether they improve antidepressant (AD) adherence or depressive symptoms. We followed 297 older veterans diagnosed with depression and provided a new AD medication prospectively for 4 months. Data include validated self-report measures and VA pharmacy records. At initial assessment, 20.5% of participants were prescribed a BZD. Those with a BZD prescription at baseline were significantly more likely than those without to have a personality disorder, schizophrenia spectrum disorder, or other anxiety disorder, and higher depressive symptom and anxiety symptom scale scores on average. In adjusted regressions, BZD use was not significantly associated with AD adherence, any improvement in depressive symptoms, or a 50% reduction in depressive symptoms. Our results suggest BZD use concurrent with AD treatment does not significantly improve depressive outcomes in older veterans.

Treatment changes among older patients with dementia treated with antipsychotics.

BACKGROUND: Prescribing practice patterns and factors associated with treatment changes in older patients initiating antipsychotic treatment for the behavioral and psychological symptoms of dementia is not well known. OBJECTIVES: The objective of this study is to study 90-day prescribing practice patterns across the three most commonly prescribed antipsychotics. METHODS: This is a retrospective study using national data from the US Department of Veterans Affairs (VA). The study included patients older than 65 years diagnosed with dementia who began outpatient treatment with an antipsychotic medication between 2005 and 2008. Patients were followed for 90 days from their antipsychotic start. The primary event of interest was changing to another psychotropic medication. Cumulative incidence of treatment change was determined with antipsychotic discontinuation and death as competing risks. Covariate-adjusted hazard ratios for treatment change were determined using competing risk regression models. RESULTS: During the study period, 15,435 patients initiated an atypical antipsychotic; 14,791 started olanzapine, quetiapine, or risperidone. Over half (55%) of the patients discontinued index treatment within 90 days, 36% continued, 3% died while on index treatment, and 6% changed to another psychotropic medication. Compared with quetiapine, the adjusted hazard of treatment change was higher by 43% (p = 0.005) for olanzapine and by 12% (p = 0.08) for risperidone. CONCLUSION: The higher hazard of treatment change with olanzapine suggests patients either responded worse to or experienced more adverse events with olanzapine compared with quetiapine.

The association between race and gender, treatment attitudes, and antidepressant treatment adherence.

OBJECTIVES: We examined the associations between treatment attitudes and beliefs with race-gender differences in antidepressant adherence. METHODS: Subjects (n = 186) were African-American and White subjects aged ≥60 years, diagnosed with clinically significant depression, and had a new outpatient primary care recommendation for antidepressant treatment. Antidepressant adherence was assessed using the Brief Medication Questionnaire. Attitudes and beliefs were assessed using the Patients Attitudes Toward and Ratings of Care for Depression, two items rating perceived medication importance, and a modified version of the Stigma Scale for Receiving Psychological Help. RESULTS: African-American men and women had significantly greater concerns about antidepressants and significantly less understanding about treatment than White women. African-American men had significantly more negative attitudes toward healthcare providers than African-American and White women. African-American women were more likely than White men and women to endorse a medication other than their antidepressant as most important. Whereas some race-gender differences were found in personal spirituality, no group differences were found in perceived stigma. In a logistic regression model adjusted for key baseline variables, White women were significantly more adherent to antidepressants than African-American women (OR = 3.05, 95% CI = 1.06-8.81). Fewer concerns about antidepressants and indicating the antidepressant as the most important medication were both significantly associated with adherence. After including either of these two variables, the adherence difference between White women and African-American women was no longer significant (OR = 2.56, 95% CI = 0.84-7.80). CONCLUSIONS: Concerns about antidepressants and the importance of antidepressant medication are associated with adherence and are potentially modifiable through improved patient-provider communication, psycho-education, and therapeutic interventions.

The Short-Answer Vignette Examination (SAVE): an assessment tool for the core psychiatry clerkship.

OBJECTIVE: This study aims to develop a vignette-based assessment tool for medical students on the psychiatry clerkship, with the goal of capturing knowledge and clinical reasoning. METHODS: The Short-Answer Vignette Exam (SAVE), four case vignettes with open-ended questions regarding assessment, differential diagnosis, management, and treatment, was developed for and administered to medical students rotating through psychiatry at a university medical school over one academic year (n = 169). The correlation of SAVE scores to resident/faculty evaluations (clinical rating) and Shelf exam scores were analyzed. RESULTS: SAVE scores were significantly correlated with scores on both the Shelf and Clinical Rating. By contrast, Shelf scores were not significantly related to Clinical Rating. CONCLUSION: The SAVE may measure aspects of clinical decision making not measured by the Shelf, without being redundant in what is assessed by the Clinical Rating. The SAVE provides an additional potentially useful assessment tool to evaluate medical students on the psychiatry clerkship.

Racial differences in adherence to antidepressant treatment in later life.

OBJECTIVE: Although antidepressants are an effective treatment for later-life depression, older patients often choose not to initiate or to discontinue medication treatment prematurely. Although racial differences in depression treatment preferences have been reported, little is known about racial differences in antidepressant medication adherence among older patients. DESIGN: Prospective, observational study comparing antidepressant adherence for older African American and white primary care patients. PARTICIPANTS: A total of 188 subjects age 60 and older, diagnosed with clinically significant depression with a new recommendation for antidepressant treatment by their primary care physician. MEASUREMENT: Study participants were assessed at study entry and at the 4-month follow-up (encompassing the acute treatment phase). Depression medication adherence was based on a well-validated self-report measure. RESULTS: At the 4-month follow-up, 61.2% of subjects reported that they were adherent to their antidepressant medication. In unadjusted and two of the three adjusted analyses, African American subjects (n = 82) had significantly lower rates of 4-month antidepressant adherence than white subjects (n = 106). African American women had the lowest adherence rates (44.4%) followed by African American men (56.8%), white men (65.3%), and white women (73.7%). In logistic regression models controlling for demographic, illness, and functional status variables, significant differences persisted between African American women and white women in reported 4-month antidepressant adherence (OR: 3.58, 95% CI: 1.27-10.07, Wald χ(2) = 2.42, df = 1, p <0.02). CONCLUSIONS: The results demonstrate racial and gender differences in antidepressant adherence in older adults. Depression treatment interventions for older adults should take into account the potential impact of race and gender on adherence to prescribed medications.

Genome-wide screen reveals Rab12 GTPase as a critical activator of Parkinson's disease-linked LRRK2 kinase.

Activating mutations in the leucine-rich repeat kinase 2 (LRRK2) cause Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases, particularly Rab10 and Rab8A, and we showed previously that these phosphoRabs play an important role in LRRK2 membrane recruitment and activation (Vides et al., 2022). To learn more about LRRK2 pathway regulation, we carried out an unbiased, CRISPR-based genome-wide screen to identify modifiers of cellular phosphoRab10 levels. A flow cytometry assay was developed to detect changes in phosphoRab10 levels in pools of mouse NIH-3T3 cells harboring unique CRISPR guide sequences. Multiple negative and positive regulators were identified; surprisingly, knockout of the Rab12 gene was especially effective in decreasing phosphoRab10 levels in multiple cell types and knockout mouse tissues. Rab-driven increases in phosphoRab10 were specific for Rab12, LRRK2-dependent and PPM1H phosphatase-reversible, and did not require Rab12 phosphorylation; they were seen with wild type and pathogenic G2019S and R1441C LRRK2. As expected for a protein that regulates LRRK2 activity, Rab12 also influenced primary cilia formation. AlphaFold modeling revealed a novel Rab12 binding site in the LRRK2 Armadillo domain, and we show that residues predicted to be essential for Rab12 interaction at this site influence phosphoRab10 and phosphoRab12 levels in a manner distinct from Rab29 activation of LRRK2. Our data show that Rab12 binding to a new site in the LRRK2 Armadillo domain activates LRRK2 kinase for Rab phosphorylation and could serve as a new therapeutic target for a novel class of LRRK2 inhibitors that do not target the kinase domain.

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus.

OBJECTIVES: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol. METHODS: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer's disease, Huntington's disease, Parkinson's disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART. RESULTS: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART. DISCUSSION: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.

Mortality risk with the use of atypical antipsychotics in later-life bipolar disorder.

INTRODUCTION: In recent years, concerns about the use of antipsychotic medications in dementia have grown. There is limited data on mortality risk of atypical antipsychotics for other psychiatric disorders of later life such as bipolar disorder. METHODS: Data were derived from the national Department of Veterans Affairs registries for older patients with bipolar disorder (≥65 years) with a new start of an atypical antipsychotic (risperidone, olanzapine, or quetiapine) or valproic acid and derivatives during fiscal years 2001-2008. Six-month mortality rates were compared for individual drug groups. RESULTS: The sample included 4717 patients. The risperidone cohort had the highest mortality rate (11.8 per 100 person-years) with the quetiapine and valproic acid cohorts having the lowest (5.3 and 4.6 per 100 person-years, respectively). Various methods to adjust for baseline differences including propensity models showed similar patterns. CONCLUSIONS: Among older patients with bipolar disorder, there may be differences in mortality risks among individual antipsychotic agents.

Dermatology: how to manage acne in skin of colour.

Acne vulgaris is a prevalent dermatological condition worldwide but is especially challenging to treat in individuals with skin of colour (SOC). Corresponding to Fitzpatrick skin phototypes III-VI, people of African, Asian, Middle Eastern and Hispanic ethnicity are considered to have SOC. With the additional risk of postinflammatory hyperpigmentation (PIH) as a consequence of inflammatory acne or its respective treatment, managing acne in this population holds significant importance. PIH adversely impacts self-esteem and quality of life and, thus, is usually the patient's priority of treatment. Available acne treatments are similar for all skin types. However, some are more beneficial for individuals with SOC, in particular by targeting both active acne lesions and PIH. The acne treatment literature was searched for topical and systemic treatments that were specifically studied in the SOC population. These treatments included topical agents, such as retinoids and azelaic acid, in addition to topical antibiotics and benzoyl peroxide. Newer formulations and combined regimens reported effective in reducing lesions are less likely to induce PIH and may treat pre-existing PIH. Moisturiser use, titrating doses and patient education are strategies to minimize irritation and improve adherence. In addition, systemic therapies, including oral antibiotics, isotretinoin, oral contraceptives and spironolactone, are efficacious for refractory acne or more severe cases but specific studies in SOC are lacking. Chemical peels may improve acne and target PIH directly. Overall, based on limited evidence, topical and systemic therapies are well tolerated in the SOC population but efficacy should be balanced with the risk of adverse effects. This narrative review aims to highlight formulations and combination therapies that are effective and safe for treating acne and PIH in patients with SOC.

A feed-forward pathway drives LRRK2 kinase membrane recruitment and activation.

Activating mutations in the leucine-rich repeat kinase 2 (LRRK2) cause Parkinson's disease, and previously we showed that activated LRRK2 phosphorylates a subset of Rab GTPases (Steger et al., 2017). Moreover, Golgi-associated Rab29 can recruit LRRK2 to the surface of the Golgi and activate it there for both auto- and Rab substrate phosphorylation. Here, we define the precise Rab29 binding region of the LRRK2 Armadillo domain between residues 360-450 and show that this domain, termed 'site #1,' can also bind additional LRRK2 substrates, Rab8A and Rab10. Moreover, we identify a distinct, N-terminal, higher-affinity interaction interface between LRRK2 phosphorylated Rab8 and Rab10 termed 'site #2' that can retain LRRK2 on membranes in cells to catalyze multiple, subsequent phosphorylation events. Kinase inhibitor washout experiments demonstrate that rapid recovery of kinase activity in cells depends on the ability of LRRK2 to associate with phosphorylated Rab proteins, and phosphorylated Rab8A stimulates LRRK2 phosphorylation of Rab10 in vitro. Reconstitution of purified LRRK2 recruitment onto planar lipid bilayers decorated with Rab10 protein demonstrates cooperative association of only active LRRK2 with phospho-Rab10-containing membrane surfaces. These experiments reveal a feed-forward pathway that provides spatial control and membrane activation of LRRK2 kinase activity.