Deep sequencing of proteotoxicity modifier genes uncovers a Presenilin-2/beta-amyloid-actin genetic risk module shared among alpha-synucleinopathies.

Whether neurodegenerative diseases linked to misfolding of the same protein share genetic risk drivers or whether different protein-aggregation pathologies in neurodegeneration are mechanistically related remains uncertain. Conventional genetic analyses are underpowered to address these questions. Through careful selection of patients based on protein aggregation phenotype (rather than clinical diagnosis) we can increase statistical power to detect associated variants in a targeted set of genes that modify proteotoxicities. Genetic modifiers of alpha-synuclein (ɑS) and beta-amyloid (Aß) cytotoxicity in yeast are enriched in risk factors for Parkinson's disease (PD) and Alzheimer's disease (AD), respectively. Here, along with known AD/PD risk genes, we deeply sequenced exomes of 430 ɑS/Aß modifier genes in patients across alpha-synucleinopathies (PD, Lewy body dementia and multiple system atrophy). Beyond known PD genes GBA1 and LRRK2, rare variants AD genes (CD33, CR1 and PSEN2) and Aß toxicity modifiers involved in RhoA/actin cytoskeleton regulation (ARGHEF1, ARHGEF28, MICAL3, PASK, PKN2, PSEN2) were shared risk factors across synucleinopathies. Actin pathology occurred in iPSC synucleinopathy models and RhoA downregulation exacerbated ɑS pathology. Even in sporadic PD, the expression of these genes was altered across CNS cell types. Genome-wide CRISPR screens revealed the essentiality of PSEN2 in both human cortical and dopaminergic neurons, and PSEN2 mutation carriers exhibited diffuse brainstem and cortical synucleinopathy independent of AD pathology. PSEN2 contributes to a common-risk signal in PD GWAS and regulates ɑS expression in neurons. Our results identify convergent mechanisms across synucleinopathies, some shared with AD.

Outpatient vs Inpatient Single-Port Robotic Urologic Surgery: Perioperative Outcomes and Complications.

INTRODUCTION: The da Vinci Single Port (SP) robotic surgical system has minimized the impact of surgery on patients. Hence, outpatient robotic procedures are being explored to reduce costs and improve patient experience. Here, we evaluate the perioperative outcomes and safety of same-day discharge (SDD) after surgery compared to inpatient procedures using the SP. METHODS: A total of 374 patients underwent surgery with the da Vinci SP system between January 2019 and February 2023. Surgeries were performed in a single high-volume center. Patients were either managed with a standardized outpatient or inpatient protocol. SDD clinical pathway was implemented in June 2021. Patients were assessed for discharge eligibility based on specific guidelines. Detailed instructions were provided at discharge, and patients were followed postoperatively. Baseline characteristics, perioperative data, complications, time to complication, and readmissions were assessed. RESULTS: Two hundred eight patients underwent outpatient surgery and 166 underwent inpatient surgery (total = 374). Outpatient surgery was not associated with increased postoperative complications and readmission compared to inpatient surgery. Ninety percent and 74.6% of patients experienced no complications in the outpatient and inpatient populations, respectively (P =< .001). Time to first complication was also comparable between the 2 groups (3 days [IQR 1-8] vs 10 days [IQR 4-30] for outpatient vs inpatient; P = .3). The proportion of successful SDDs increased over time, reaching 88% in October 2022. CONCLUSIONS: Outpatient surgery using the da Vinci SP is safe and feasible, without increasing postoperative complications compared to standard inpatient surgery.

Identification of 27 allele-specific regulatory variants in Parkinson's disease using a massively parallel reporter assay.

Genome wide association studies (GWAS) have identified a number of genomic loci that are associated with Parkinson's disease (PD) risk. However, the majority of these variants lie in non-coding regions, and thus the mechanisms by which they influence disease development, and/or potential subtypes, remain largely elusive. To address this, we used a massively parallel reporter assay (MPRA) to screen the regulatory function of 5254 variants that have a known or putative connection to PD. We identified 138 loci with enhancer activity, of which 27 exhibited allele-specific regulatory activity in HEK293 cells. The identified regulatory variant(s) typically did not match the original tag variant within the PD associated locus, supporting the need for deeper exploration of these loci. The existence of allele specific transcriptional impacts within HEK293 cells, confirms that at least a subset of the PD associated regions mark functional gene regulatory elements. Future functional studies that confirm the putative targets of the empirically verified regulatory variants will be crucial for gaining a greater understanding of how gene regulatory network(s) modulate PD risk.

In-silico, Synthesis, Characterization, and In-vitro Studies on Benzylidene-based 2-chloroquinolin Derivatives as Free Radical Scavengers in Parkinson's Disease.

Parkinson's disease is the loss of dopaminergic neurons in the substantial nigra part of the brain leading to neurodegeneration. Whereas, reactive oxygen species and mitochondrial impairment are considered to be the major pathophysiology of neurodegeneration. The benzylidene-based 2-chloroquinolin derivatives were synthesized and characterized by FT-IR, NMR, and MS spectrometry which were screened using various in-silico approaches. The designed compounds were further assessed using in-vitro cytotoxicity assay by the MTT method, DPPH assay, and Glutathione measurements in the SHSY5Y neuroblastoma cell lines. The compounds JD-7 and JD-4 were found to have a binding affinity of - 7.941 and - 7.633 kcal/mol with an MMGBSA score of - 64.614 and - 62.817 kcal/mol. The compound JD-7 showed the highest % Cell viability of 87.64% at a minimal dose of 125 µg/mL by the MTT method. The neurotoxicity effects were observed at increasing concentrations from 0 to 125, 250, and 500 µg/mL. Further, free radical scavenging activity for the JD-7 was found to be 36.55 at lowest 125 µg/mL concentrations. At 125 µg/mL, GSH % and GSSG % were found to be increasing in rotenone treatment, whereas JD-7 and JD-4 were found in the downregulation of glutathione level in the pre-treated rotenone SHSY5Y neuroblastoma cell lines. The benzylidene-based chloroquinolin derivatives were synthesized, and among the compounds JD-1 to JD-13, the compounds JD-7, and JD-4 were found to have having highest % cell viability, free radical scavenging molecules, and glutathione levels in the SHSY5Y neuroblastoma cell lines and could be used as free radical scavengers in Parkinson's disease.

Single port robot-assisted radical and simple prostatectomy: a systematic review and meta-analysis.

BACKGROUND: Aim of our study was to review the current evidence on single port robot-assisted radical prostatectomy (SP-RARP) and SP robot-assisted simple prostatectomy (SP-RASP) procedures. METHODS: A comprehensive bibliographic search on multiple databases was conducted in July 2023. Studies were included if they assessed patients with non-metastatic prostate cancer or candidate for benign prostatic hyperplasia surgery (P) who underwent SP-RARP or SP-RASP, respectively, (I), compared or not with other surgical techniques (C), evaluating perioperative, oncological, or functional outcomes (O). Prospective and retrospective original articles were included (S). A meta-analysis of comparative studies between SP-RARP and MP-RARP was performed. RESULTS: A total of 21 studies investigating 1400 patients were included in our systematic review, 18 were related to SP-RARP while 3 to SP-RASP. Only 8 comparative studies were eligible for meta-analysis. Mean follow-up was 8.1 (±5.8) months. Similar outcomes were observed for SP-RARP and MP-RARP in terms of operative time, catheterization time, pain score, complications rate, continence and potency rates, positive surgical margin, and biochemical recurrence. Length of hospital stay was shorter in the SP group after sensitivity analysis (WMD -0.58, 95% IC -1.17 to -0.9, p < 0.05). Subgroup analysis by extraperitoneal approach did not show any statistical difference, except for a lower positive margins rate in the SP extraperitoneal technique compared to MP-RARP. Overall, SP-RASP exhibited shorter hospital stay and lower rate of de novo urinary incontinence when compared to other techniques, while no differences were reported in terms of postoperative International Prostate Symptom Score, post void residual and maximum flow. CONCLUSIONS: Overall comparable oncological, functional, and perioperative outcomes can be achieved with SP platform. Subgroup analysis by different approaches did not reveal significant variations in outcomes. However, the retrospective nature of the studies, the limited follow-up, and the relatively small sample size of selected Centers may impact these results.

Application of the single-port robotic platform during radical nephroureterectomy for upper tract urothelial carcinoma: feasibility of the single-port robot in the multi-quadrant setting.

Urothelial carcinoma of the upper tract (UTUC) is a malignancy that accounts for 5-10% of all urothelial carcinomas. Radical surgery is the primary treatment option due to the high rate of invasive stages at the time of diagnosis. Nephroureterectomy (NU) with bladder cuff excision is the current standard of care. While laparoscopic NU has been established since 1991, many centres still perform open surgery due to the complexity of laparoscopic instrumentation and the steep learning curve for excising the bladder cuff. With the increasing adoption of the multi-port (MP) robotic surgery, NU has increasingly been performed using this platform. The use of MP robotic systems for NU has been challenged by the need for patient repositioning and/or redocking of the robot, which can consume valuable operative time. The transition from the daVinci Si to the daVinci Xi system has seen a noticeable reduction in redocking and patient repositioning. However, owing to the multi-quadrant nature of the surgery in question, the use of multiple ports and external instrument clashing are still persistent problems. Moreover, there is a growing interest in utilizing a retroperitoneal approach for robot-assisted NU due to its potential benefits such as improved control of hilar structures, reduction of blood loss, shorter operative time and hospital stay, reduced complications and decreased postoperative discomfort. The application of the daVinci single-port (SP) robotic platform during radical NU for UTUC is feasible and has the potential to improve the current surgical approach. Indeed, the use of a SP platform may solve the problem of patient repositioning and redocking of the robot, improve superficial aesthetic outcome and minimize external instrument clashing. While maintaining an optimal oncological control, the retroperitoneal approach, which has been difficult to replicate and adopt using the MP approach, may become standard practice. However, more studies are needed to confirm the benefit of this approach and ultimately determine the impact of the daVinci SP on the management of UTUC.

Robot-assisted Surgery in the Field of Urology: The Most Pioneering Approaches 2015-2023.

Robot-assisted surgery has emerged as a transformative technology, revolutionizing surgical approaches and techniques that decades ago could barely be imagined. The field of urology has taken charge in pioneering a new era of minimally invasive surgery with the ascent of robotic systems which offer enhanced visualization, precision, dexterity, and enabling surgeons to perform intricate maneuvers with improved accuracy. This has led to improved surgical outcomes, including reduced blood loss, lower complication rates, and faster patient recovery. The aim of our review is to present an evidence-based critical analysis on the most pioneering robotic urologic approaches described over the last eight years (2015-2023).

Biased signalling is structurally encoded as an autoproteolysis event in adhesion G protein-coupled receptor Latrophilin-3/ADGRL3.

Adhesion G protein-coupled receptors (aGPCRs) possess a unique topology, including the presence of a GPCR proteolysis site (GPS), which, upon autoproteolysis, generates two functionally distinct fragments that remain non-covalently associated at the plasma membrane. A proposed activation mechanism for aGPCRs involves the exposure of a tethered agonist, which depends on cleavage at the GPS. However, this hypothesis has been challenged by the observation that non-cleavable aGPCRs exhibit constitutive activity, thus making the function of GPS cleavage widely enigmatic. In this study, we sought to elucidate the function of GPS-mediated cleavage through the study of G protein coupling with Latrophilin-3/ADGRL3, a prototypical aGPCR involved in synapse formation and function. Using BRET-based G protein biosensors, we reveal that an autoproteolysis-deficient mutant of ADGRL3 retains constitutive activity. Surprisingly, we uncover that cleavage deficiency leads to a signalling bias directed at potentiating the activity of select G proteins such as Gi2 and G12/13. These data unveil the underpinnings of biased signalling for aGPCRs defined by GPS autoproteolysis.

Single-Port Robot-Assisted Radical Prostatectomy: Where Do We Stand?

In 2018, the da Vinci Single Port (SP) robotic system was approved by the US Food and Drug Administration for urologic procedures. Available studies for the application of SP to prostate cancer surgery are limited. The aim of our study is to summarize the current evidence on the techniques and outcomes of SP robot-assisted radical prostatectomy (SP-RARLP) procedures. A narrative review of the literature was performed in January 2023. Preliminary results suggest that SP-RALP is safe and feasible, and it can offer comparable outcomes to the standard multiport RALP. Extraperitoneal and transvesical SP-RALP appear to be the two most promising approaches, as they offer decreased invasiveness, potentially shorter length of stay, and better pain control. Long-term, high-quality data are missing and further validation with prospective studies across different sites is required.

Simplifying Retroperitoneal Robotic Single-port Surgery: Novel Supine Anterior Retroperitoneal Access.

BACKGROUND: Multiport robotic surgery in the retroperitoneum is limited by the bulky robotic frame and clashing of instruments. Moreover, patients are placed in the lateral decubitus position, which has been linked to complications. OBJECTIVE: To assess the feasibility and safety of a supine anterior retroperitoneal access (SARA) technique with the da Vinci Single-Port (SP) robotic platform. DESIGN, SETTING, AND PARTICIPANTS: Between October 2022 and January 2023, 18 patients underwent surgery using the SARA technique for renal cancer, urothelial cancer, or ureteral stenosis. Perioperative variables were prospectively collected and outcomes were assessed. SURGICAL PROCEDURE: With the patient in a supine position, a 3-cm incision is made at the McBurney point and the abdominal muscles are dissected. Finger dissection is used to develop the retroperitoneal space for the da Vinci SP access port. After docking, the first step is to dissect retroperitoneal tissue to reveal the psoas muscle. This allows identification of the ureter, the inferior renal pole, and the hilum. MEASUREMENTS: A descriptive statistical analysis was performed. Data collected included demographics, operative time, warm ischemia time (WIT), surgical margin status, complications, length of hospital stay, 30-d Clavien-Dindo complications, and postoperative narcotic use. RESULTS AND LIMITATIONS: Twelve patients underwent partial nephrectomy (PN) and two each underwent pyeloplasty, radical nephroureterectomy, and radical nephrectomy. In the PN group, mean age was 57 yr (interquartile range [IQR] 30-73), median body mass index was 32 kg/m2 (IQR 17-58), and 25% had stage ≥3 chronic kidney disease. The median Charlson comorbidity index was 3 (IQR 0-7) and 75% of PN patients had an American Society of Anesthesiologists score ≥3. The median RENAL score was 5 (IQR 4-7). The median WIT was 25 min (IQR 16-48) and the median tumor size was 35 mm (IQR 16-50). The median estimated blood loss was 105 ml (IQR 20-400) and the median operative time was 160 min (IQR 110-200). Positive surgical margins were found in one patient. In the overall cohort, one patient was readmitted and managed conservatively; 83% of the PN group were discharged on the same day as their surgery, with the remainder discharged the next day. At 7 d after surgery, no patients reported narcotic use. CONCLUSIONS: The SARA approach is feasible and safe. Larger studies are needed to confirm this approach as a one-step solution for upper urinary tract surgery. PATIENT SUMMARY: We assessed initial outcomes of a novel approach for accessing the retroperitoneum (the space behind the abdominal cavity and in front of the back muscles and spine) during robot-assisted surgery in the upper urinary tract. The patient is placed on their back and surgery is performed with a single-port robot. Our results show that this approach was feasible and safe, with low complication rates, less postoperative pain, and earlier discharge. This is a promising start, but larger studies are needed to confirm our findings.

Extragalactic Science with the Orbiting Astronomical Satellite Investigating Stellar Systems (OASIS) Observatory.

The Orbiting Astronomical Satellite for Investigating Stellar Systems (OASIS), a proposed Astrophysics MIDEX-class mission concept, has an innovative 14-meter diameter inflatable primary mirror that will provide the sensitivity to study far-infrared continuum and line emission from galaxies at all redshifts with high spectral resolution heterodyne receivers. OASIS will have the sensitivity to follow the water trail from galaxies to the comets that create oceans. It will bring an understanding of the role of water in galaxy evolution and its part of the oxygen budget, by measuring water emission from local to intermediate redshift galaxies, observations that have not been possible from the ground. Observation of the ground-state HD line will accurately measure gas mass in a wide variety of astrophysical objects. Thanks to its exquisite spatial resolution and sensitivity, OASIS will, during its one-year baseline mission, detect water in galaxies with unprecedented statistical significance. This paper reviews the extragalactic science achievable and planned with OASIS.

Electrical conductivity and electrochemical studies of Cr-doped MoO3 nanoflakes for energy storage applications.

The growing demand for electricity has increased the interest of the researchers towards exploration of energy storing devices (ESDs). With the motif for developing electrochemical energy storage devices, this research work is focussed on the study of MoO3 nanoparticles and its doping with chromium as an efficient electrode material for energy storage applications. The nanoparticles were synthesized by hydrothermal method and were examined by powder X-ray diffraction, which determined the thermodynamically stable orthorhombic phase of MoO3, and their morphologies were examined using scanning electron microscopy displaying flake-like structures. The typical vibrational bands of Mo-O were identified from Infra-red and Raman spectral analysis. The ultra violet diffuse reflectance spectra revealed the decrease in optical band gap after doping with chromium. The temperature dependent AC and DC conductivities were enhanced on doping. Electrochemical behaviour of the nanoparticles was probed by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) measurements and galvanostatic charge-discharge (GCD) analysis for which specific capacitance (C sp) value of 334 Fg-1 was achieved for Cr-doped MoO3 nanoparticles. The electrochemical performance of the sample was found to be increased after doping with Cr.

Identifying robust and reliable volatile organic compounds in human sebum for biomarker discovery.

Sebum from sebaceous glands is a rich source of volatile organic compounds (VOCs) that can readily be sampled non-invasively from the surface of skin. The VOC profiles of sebum can then be used to obtain information regarding different medical conditions including diabetes and Parkinson's Disease. However, the effects of sampling approaches and environmental factors on sebum VOC profiles are not established and the confident attribution of VOCs to disease states needs to be free of extraneous influences such as sampling materials and preparatory conditions. Here, we investigated a more standardised skin swab sampling approach for profiling sebum VOCs from healthy human subjects using thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS). Using a standard GC-MS method for the chemical analysis of sebum swabs, a surprisingly high number of VOCs originate from 'blank' medical swab material alone (up to 74 VOCs) and from the ambient environment (up to 29 VOCs) based on control experiments. We found that heat-treatment of medical swabs prior to GC-MS reduced the number of VOCs detected from 'blank' swabs and improved the reproducibility of VOC profiling, however significant VOC absorption can still occur from environmental exposure to ambient air. VOCs identified in 'blank' swabs consisted predominantly of hydrocarbons, esters, and silicon-based compounds and depended strongly on the material used (cotton and polyester-rayon). Environmental VOCs found to absorb to swabs from the ambient air during sampling included 1-butylheptyl-benzene and hexadecanoic acid methyl ester as well as exogenous VOCs such as isopropyl palmitate and isopropyl myristate. In contrast, sebum VOCs consisted primarily of esters, alcohols, ketones, and aldehydes. 23 and 18 VOCs were identified in sebum collected using polyester-rayon and cotton-based medical swabs, respectively, with 14 VOCs common to both swabs. The effect of subject bathing prior to sebum sampling had minimal impact on the VOC profiles. However, individual differences owing to external factors such as skin type, diet, and exercise will likely influence sebum production. This study highlights the importance of using rigorous controls in sebum sampling, and recommendations are provided for future research involving sebum VOC analysis. For example, the use of sebum sample replicates across multiple days, and the use of control swabs during sample collection is required to confirm the origin and reliability of sebum VOCs. It is anticipated that these recommendations in conjunction with a library of well-established VOCs from medical swabs will further strengthen biomarker identification resulting from sebum VOC analysis.

Thwarting of Lphn3 Functions in Cell Motility and Signaling by Cancer-Related GAIN Domain Somatic Mutations.

Cancer progression relies on cellular transition states accompanied by changes in the functionality of adhesion molecules. The gene for adhesion G protein-coupled receptor latrophilin-3 (aGPCR Lphn3 or ADGRL3) is targeted by tumor-specific somatic mutations predominantly affecting the conserved GAIN domain where most aGPCRs are cleaved. However, it is unclear how these GAIN domain-altering mutations impact Lphn3 function. Here, we studied Lphn3 cancer-related mutations as a proxy for revealing unknown GAIN domain functions. We found that while intra-GAIN cleavage efficiency was unaltered, most mutations produced a ligand-specific impairment of Lphn3 intercellular adhesion profile paralleled by an increase in cell-matrix actin-dependent contact structures for cells expressing the select S810L mutation. Aberrant remodeling of the intermediate filament vimentin, which was found to coincide with Lphn3-induced modification of nuclear morphology, had less impact on the nuclei of S810L expressing cells. Notoriously, receptor signaling through G13 protein was deficient for all variants bearing non-homologous amino acid substitutions, including the S810L variant. Analysis of cell migration paradigms revealed a non-cell-autonomous impairment in collective cell migration indistinctly of Lphn3 or its cancer-related variants expression, while cell-autonomous motility was potentiated in the presence of Lphn3, but this effect was abolished in S810L GAIN mutant-expressing cells. These data identify the GAIN domain as an important regulator of Lphn3-dependent cell motility, thus furthering our understanding of cellular and molecular events linking Lphn3 genetic somatic mutations to cancer-relevant pathogenesis mechanisms.

Multidisciplinary team referral at diagnosis for patients with non-metastatic renal cell carcinoma.

BACKGROUND: To date, multidisciplinary team (MDT) evaluation, enrollment in trials evaluating the role of perioperative therapies and deferred active treatments represent accepted strategies for patients with Renal Cell Carcinoma (RCC), which are under investigation to maximize cancer control and implement health care policies and value-based care. Here, we aimed to identify subgroups of patients with RCC who may benefit from early referral for MDT evaluation at diagnosis in light of an increased risk of recurrence relative to the risk of dying of other causes. METHODS: We relied on a prospective dataset including patients diagnosed with RCC from 1998 to 2019 and treated by means of surgery alone at a tertiary referral center. The risk of other cause mortality (OCM) was evaluated against the risk of distant metastasis over time by means of the Weibull regression. Patients were stratified based on clinical stage (cT1a; cT1b; cT2; cT3-4), age (<60; 60-70; >70) and comorbidities [Charlson comorbidity index (CCI) 0 vs. ≥1]. For each combination of cT stage, age, and CCI, the potential need for an MDT referral was defined when the risk of recurrence exceeded the risk of OCM within the lower limit of the 95% CI of the meantime to recurrence. MAIN FINDINGS: Overall, 1,162 (51%) patients had no comorbidities. Median follow-up was 7 years. Patients who would benefit most from an MDT evaluation are those diagnosed with A) cT3-4 disease (any age or comorbidity) or B) cT2 cancers if healthy and younger than 70 years or younger than 60 years with at least 1 comorbidity or C) cT1b if younger than 60 years and without comorbidities. CONCLUSIONS: Our findings can help selecting the optimal candidates for multidisciplinary evaluations and to consider RCC patients for clinical trials, deferred treatment, and treatment policy improvement. Also, our findings can be useful in the case of major healthcare disruptions, such as pandemics.

Convergent selective signaling impairment exposes the pathogenicity of latrophilin-3 missense variants linked to inheritable ADHD susceptibility.

Latrophilin-3 (Lphn3; also known as ADGRL3) is a member of the adhesion G Protein Coupled Receptor subfamily, which participates in the stabilization and maintenance of neuronal networks by mediating intercellular adhesion through heterophilic interactions with transmembrane ligands. Polymorphisms modifying the Lphn3 gene are associated with attention-deficit/hyperactivity disorder (ADHD) in children and its persistence into adulthood. How these genetic alterations affect receptor function remains unknown. Here, we conducted the functional validation of distinct ADHD-related Lphn3 variants bearing mutations in the receptor's adhesion motif-containing extracellular region. We found that all variants tested disrupted the ability of Lphn3 to stabilize intercellular adhesion in a manner that was distinct between ligands classes, but which did not depend on ligand-receptor interaction parameters, thus pointing to altered intrinsic receptor signaling properties. Using G protein signaling biosensors, we determined that Lphn3 couples to Gαi1, Gαi2, Gαs, Gαq, and Gα13. However, all ADHD-related receptor variants consistently lacked intrinsic as well as ligand-dependent Gα13 coupling efficiency while maintaining unaltered coupling to Gαi, Gαs, and Gαq. Consistent with these alterations, actin remodeling functions as well as actin-relevant RhoA signaling normally displayed by the constitutively active Lphn3 receptor were impeded by select receptor variants, thus supporting additional signaling defects. Taken together, our data point to Gα13 selective signaling impairments as representing a disease-relevant pathogenicity pathway that can be inherited through Lphn3 gene polymorphisms. This study highlights the intricate interplay between Lphn3 GPCR functions and the actin cytoskeleton in modulating neurodevelopmental cues related to ADHD etiology.

Redefining the hypotheses driving Parkinson's diseases research.

Parkinson's disease (PD) research has largely focused on the disease as a single entity centred on the development of neuronal pathology within the central nervous system. However, there is growing recognition that PD is not a single entity but instead reflects multiple diseases, in which different combinations of environmental, genetic and potential comorbid factors interact to direct individual disease trajectories. Moreover, an increasing body of recent research implicates peripheral tissues and non-neuronal cell types in the development of PD. These observations are consistent with the hypothesis that the initial causative changes for PD development need not occur in the central nervous system. Here, we discuss how the use of neuronal pathology as a shared, qualitative phenotype minimises insights into the possibility of multiple origins and aetiologies of PD. Furthermore, we discuss how considering PD as a single entity potentially impairs our understanding of the causative molecular mechanisms, approaches for patient stratification, identification of biomarkers, and the development of therapeutic approaches to PD. The clear consequence of there being distinct diseases that collectively form PD, is that there is no single biomarker or treatment for PD development or progression. We propose that diagnosis should shift away from the clinical definitions, towards biologically defined diseases that collectively form PD, to enable informative patient stratification. N-of-one type, clinical designs offer an unbiased, and agnostic approach to re-defining PD in terms of a group of many individual diseases.