Parkinson’s disease (PD) is a progressive neurodegenerative disorder known for the typical motor features associated. Pathologically, it is characterized by the intracellular accumulation of alpha-synuclein (aSyn) in Lewy bodies and Lewy neurites. Currently, there are no established biochemical markers for diagnosing or for following disease progression, a major limitation for the clinical practice. Posttranslational modifications (PTMs) in aSyn have been identified and implicated on its pathobiology. Since aSyn is abundant in blood erythrocytes, we aimed to evaluate whether PTMs of aSyn in the blood might hold value as a biomarker for PD. We examined 58 patients with PD and 30 healthy age-matched individuals. We found that the levels of Y125 phosphorylated, Y39 nitrated, and glycated aSyn were increased in PD, while those of SUMO were reduced. A combinatory analysis of the levels of these PTMs resulted in an increased sensitivity, with an area under curve (AUC) of 0.843 for PD versus healthy controls, and correlated with disease severity and duration. We conclude that the levels of these selected PTMs hold strong potential as biochemical markers for PD. Ultimately, our findings might facilitate the monitoring of disease progression in clinical trials, opening the possibility for developing more effective therapies against PD.

Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemic stage in which B-cell precursors display self-renewal ability, initiating leukemia resembling PAX5 P80R or Ph-like human B-ALL. Full transformation associates with transcriptional upregulation of oncogenes such as Myc or Bcl2, downregulation of tumor suppressors such as Ikzf1 or Arid2, and major IL-7R signaling upregulation (involving JAK/STAT5 and PI3K/mTOR), required for leukemia cell viability. Accordingly, maximal signaling drives full penetrance and early leukemia onset in homozygous IL7R mutant animals. Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are potential treatment avenues for IL-7R-related cases. Our model, a resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.

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BackgroundHandicap is a patient‐centered measure of health status that encompasses the impact of social and physical environment on daily living, having been assessed in advanced and late‐stage Parkinson's Disease (PD).ObjectiveTo characterize the handicap of a broader sample of patients.MethodsA cross‐sectional study of 405 PD patients during the MDS‐UPDRS Portuguese validation study, using the MDS‐UPDRS, Unified Dyskinesias Rating Scale, Nonmotor symptoms questionnaire, PDQ‐8 and EQ‐5D‐3L. Handicap was measured using the London Handicap Scale (LHS).ResultsMean age was 64.42 (±10.3) years, mean disease duration 11.30 (±6.5) years and median HY 2 (IQR, 2–3). Mean LHS was 0.652 (±0.204); “Mobility,” “Occupation” and “Physical Independence” were the most affected domains. LHS was significantly worse in patients with longer disease duration, older age and increased disability. In contrast, PDQ‐8 did not differentiate age groups. Handicap was significantly correlated with disease duration (r = −0.35), nonmotor experiences of daily living (EDL) (MDS‐UPDRS‐I) (r = −0.51), motor EDL (MDS‐UPDRS‐II) (r = −0.69), motor disability (MDS‐UPDRS‐III) (r = −0.49), axial signs of MDS‐UPDRS‐III (r = −0.55), HY (r = −0.44), presence of nonmotor symptoms (r = −0.51) and PDQ‐8 index (r = −0.64) (all P < 0.05). Motor EDL, MDS‐UPDRS‐III and PDQ‐8 independently predicted Handicap (adjusted R2 = 0.582; P = 0.007).ConclusionsThe LHS was easily completed by patients and caregivers. Patients were mild‐moderately handicapped, which was strongly determined by motor disability and its impact on EDL, and poor QoL. Despite correlated, handicap and QoL seem to differ in what they measure, and handicap may have an added value to QoL. Handicap seems to be a good measure of perceived‐health status in a broad sample of PD.