Integrating Long-Read Structural Variant Analysis with single-nucleus RNA-seq to Elucidate Gene Expression Effects in Disease
By onLong-read sequencing in PD brain samples identified 74,552 structural variants. Integrating RNA sequencing data revealed SVs near PD-related genes impacting cell type-specific expression, highlighting the importance of SVs in complex diseases.
Modeling cis-regulatory variation in human brain enhancers across a large Parkinson’s Disease cohort
By onGWAS have linked more than hundred non-coding genomic loci to Parkinson’s disease (PD) risk. Here, we establish a unique resource and new sequence modeling strategies to interpret functional non-coding variation in the human brain.
ATP13A2 Loss of Function-Driven Polyamine Dysregulation Induces SAM Depletion and Epigenetic Astrocyte Toxicity
By onLoss of ATP13A2 function leads to lysosomal polyamine sequestration, depleting cytosolic polyamines in astrocytes. This triggers compensatory polyamine biosynthesis, diverting SAM from DNA methylation and promoting neuroinflammation.
Dopamine release from Parkinson’s patient-derived neurons is disrupted due to impaired synaptic vesicle loading
By onHuman Parkinson's patient neurons with SNCA-triplication mutation exhibit reduced dopamine release due deficits in dopamine loading and handling.
TEsingle enables locus-specific transposable element expression analysis at single-cell resolution
By onTEsingle is a tool for analyzing transposable elements (TE) and gene expression in single-cell data. The tool reveals cell-type specific TE expression in Parkinson's Disease patients' brain tissues.
Selective loss of Primary Cilia and Neurotrophic Signaling in G51D α-Synuclein Mice Highlights a Common Pathway to Parkinson’s Disease
By onG51D α-synuclein mice mimic disease symptoms, showing cilia loss in specific neurons and impaired neurotrophic signaling, contributing to disease progression. This highlights the role of ciliary dysfunction in Parkinson’s.
Cardiac-sympathetic state predicts action restraint, gated by demonstrated agency
By onIn healthy humans, beat-to-beat cardiac contractility during incentivized reaching predicts action restraint. Cardiac-sympathetic outflow flexibly shapes speed–accuracy tradeoffs under reward and loss contexts, beyond simple action mobilization.
Evaluation Of The Rims2 Locus As A Risk Locus For Parkinson’s Disease Dementia
By onLiu et al. found RIMS2 locus linked to dementia in Parkinson's disease. Our study with 2536 individuals found no association with RIMS2 or other loci. More research is needed to uncover biological factors influencing Parkinson's dementia.
Parkinson’s Progression Markers Initiative: A Milestone-Based Strategy to Monitor PD Progression
By onChallenge: Identifying a meaningful progression metric for Parkinson's disease (PD) that reflects heterogeneity remains a challenge. Objective: To assess the frequency and baseline predictors of progression to clinically relevant motor and non-motor PD milestones. Methods: Using data from the Parkinson's Progression Markers Initiative (PPMI) de novo PD cohort, we monitored 25 milestones across six domains ("walking and balance"; "motor complications"; "cognition"; "autonomic dysfunction"; "functional dependence"; "activities of daily living"). Milestones were intended to be severe enough to reflect meaningful disability. We assessed the proportion of participants reaching any milestone; evaluated which occurred most frequently; and conducted a time-to-first-event analysis exploring whether baseline characteristics were associated with progression. Results: Half of participants reached at least one milestone within five years. Milestones within the cognitive, functional dependence, and autonomic dysfunction domains were reached most often. Among participants who reached a milestone at an annual follow-up visit and remained active in the study, 82% continued to meet criteria for any milestone at one or more subsequent annual visits and 55% did so at the next annual visit. In multivariable analysis, baseline features predicting faster time to reaching a milestone included age (p<0.0001), greater MDS-UPDRS total scores (p<0.0001), higher GDS-15 depression scores (p=0.0341), lower dopamine transporter binding (p=0.0043), and lower CSF total α-synuclein levels (p=0.0033). Symptomatic treatment was not significantly associated with reaching a milestone (p=0.1639). Conclusions: Clinically relevant milestones occur frequently, even in early PD. Milestones were significantly associated with baseline clinical and biological markers, but not with symptomatic treatment. Further studies are necessary to validate these results, further assess the stability of milestones, and explore translating them into an outcome measure suitable for observational and therapeutic studies.
Post-fibrillization nitration of alpha-synuclein abolishes its seeding activity and pathology formation in primary neurons and in vivo
By onIncreasing evidence points to post-translational modifications (PTMs) as key regulators of alpha-synuclein (α-Syn) function in health and disease. However, whether these PTMs occur before or after α-Syn pathology formation and their role in regulating α-Syn toxicity remain unclear. In this study, we demonstrate that post-fibrillization nitration of α-Syn fibrils induced their fragmentation, modified their surface and dynamic properties but not their structure, and nearly abolished their seeding activity in primary neurons and in vivo. Furthermore, we show that the dynamic and surface properties of the fibrils, rather than simply their length, are important determinants of α-Syn fibril seeding activity. Altogether, our work demonstrates that post-aggregation modifications of α-Syn may provide novel approaches to target a central process that contributes to pathology formation and disease progression. Finally, our results suggest that the pattern of PTMs on pathological aggregates, rather than simply their presence, could be a key determinant of their toxicity and neurodegeneration. This calls for reconsidering current approaches relying solely on quantifying and correlating the level of pathology to assess the efficacy of novel therapies, as not all α-Syn aggregates in the brain are pathogenic.
Functional characterization of ATP13A2 variants associated with distinct neurodegenerative disorders
By onATP13A2 is a late endolysosomal transporter that exports the polyamines spermine and spermidine from the organellar lumen to the cytosol. Loss-of-function variants in ATP13A2 are causative for Kufor-Rakeb syndrome (KRS, a recessive juvenile-onset parkinsonism with dementia) and have also been identified in early-onset PD (EOPD) and hereditary spastic paraplegia (HSP). Furthermore, candidate pathogenic ATP13A2 variants have been identified in neuronal ceroid lipofuscinosis (NCL; M854R), multiple system atrophy (MSA; Y1020C) and amyotrophic lateral sclerosis (ALS; I411M) suggesting that ATP13A2 may be implicated in a broader range of neurodegenerative disorders. Since the functional consequences of the NCL, MSA, and ALS variants have not yet been examined, we here characterized these ATP13A2 variants in terms of subcellular localization, cellular polyamine uptake, and transport activity. We found that the homozygous NCL-associated M854R variant results in an instable protein with low expression levels, leading to complete loss of ATPase and cellular polyamine uptake activity. The heterozygous MSA-linked Y1020C variant is properly localized and presents only partially decreased ATPase activity without affecting cellular polyamine uptake. The ALS-associated I411M variant is also correctly localized and exhibits a minor effect on cellular polyamine uptake, however, without a significant impact on ATPase activity. Taken together, only the homozygous NCL variant of ATP13A2 causes a complete loss-of-function, validating that ATP13A2 dysfunction is implicated in NCL. The ALS and MSA variants only presented a subtle functional defect, questioning whether these heterozygous variants are pathogenic and whether ATP13A2 dysfunction may cause MSA or ALS.
Genome-wide association identified novel etiological insights associated with Parkinson’s disease in African and African admixed populations
By onUnderstanding the genetic mechanisms underlying diseases in ancestrally diverse populations is a critical step towards the realization of the global application of precision medicine. Here we perform a comprehensive genome-wide assessment of Parkinson’s disease (PD) in African and African admixed ancestry, characterizing population-specific risk, differential haplotype structure and admixture, coding and structural genetic variation and polygenic risk profiling. We identified a novel common risk factor for PD and age at onset at the GBA1 locus, that was found to be rare in non-African/African admixed populations.
L1 retrotransposons drive human neuronal transcriptome complexity and functional diversification
By onThe genetic mechanisms underlying the expansion in size and complexity of the human brain remains poorly understood. L1 retrotransposons are a source of divergent genetic information in hominoid genomes, but their importance in physiological functions and their contribution to human brain evolution is largely unknown. Using multi-omic profiling we here demonstrate that L1-promoters are dynamically active in the developing and adult human brain. L1s generate hundreds of developmentally regulated and cell-type specific transcripts, many which are co-opted as chimeric transcripts or regulatory RNAs. One L1-derived lncRNA, LINC01876, is a human-specific transcript expressed exclusively during brain development. CRISPRi-silencing of LINC01876 results in reduced size of cerebral organoids and premature differentiation of neural progenitors, implicating L1s in human-specific developmental processes. In summary, our results demonstrate that L1-derived transcripts provide a previously undescribed layer of primate- and human-specific transcriptome complexity that contributes to the functional diversification of the human brain.
Quantitative mapping of autophagic cargo during nutrient stress reveals YIPF3-YIPF4 as membrane receptors for Golgiphagy
By onMacroautophagy degrades cellular macromolecules during nutrient stress, providing building blocks and remodeling the proteome. YIPF3 and YIPF4 are identified as receptors for Golgiphagy, crucial for eliminating Golgi membrane proteins.
Splicing accuracy varies across human introns, tissues and age
By onThis in-depth characterization of mis-splicing can have important implications for our understanding of the role of splicing inaccuracies in human disease and the interpretation of long-read RNA-sequencing data.
Towards a phenome-wide view of Parkinson’s disease
By onMany studies have examined the relation between PD and environmental variables serially --- one candidate association at a time. In the real world however, both environmental exposures and patients are much more complex, including correlated environmental exposures, polypharmacy, and complex comorbidities. Here we begin to characterize a holistic view of environmental, health, and pharmacological traits linked to patients with PD.
Urinary bis(monacylglycerol) phosphate (BMP) levels are higher in LRRK2 and GBA1 variant carriers but do not predict disease progression in PPMI cohorts
By onWe quantified concentrations of three isoforms of the endolysosomal lipid, bis(monoacylglycerol) phosphate (BMP) in urine of deeply phenotyped cohorts in the Parkinson’s Progression Markers Initiative: LRRK2 G2019S PD (N = 134) and non-manifesting carriers (NMC) (G2019S + NMC; N = 182), LRRK2 R1441G PD (N = 15) and R1441G + NMC (N = 15), GBA1 N409S PD (N = 76) and N409S + NMC (N = 178), sporadic PD (sPD, N = 379) and healthy controls (HC) (N = 190). Effects of each mutation and disease status were analyzed using nonparametric methods. Longitudinal changes in BMP levels were analyzed using linear mixed models. At baseline, all LRRK2 carriers had 3-7x higher BMP levels compared to HC, irrespective of the disease status. GBA1 N409S carriers also showed significant, albeit smaller, elevation (~ 30–40%) in BMP levels compared to HC. In LRRK2 G2019S PD, urinary BMP levels remained stable over two years. Furthermore, baseline BMP levels did not predict disease progression as measured by striatal DaT imaging, MDS-UPDRS III Off or MoCA in any of the cohorts. These data support the utility of BMP as a target modulation biomarker in therapeutic trials of genetic and sPD but not as a prognostic or disease progression biomarker.
Astrocytic LRRK2 Controls Synaptic Connectivity through ERM Phosphorylation
By onThis study shows that the Lrrk2 gene affects astrocyte morphology by regulating ERM protein phosphorylation, which when reduced, restores synaptic function in PD, suggesting astrocytes as potential therapeutic targets.
LRRK2 regulates the activation of the unfolded protein response and antigen presentation in macrophages during inflammation
By onAbsence of PINK1 leads to MitAP over-activation engaging autoimmune mechanisms. This pathway is induced by TLR4, cGAS-STING, and UPR activation in response to inflammatory signals. LRRK2 and STING regulate transition from innate to adaptive immunity
LRRK2-G2019S Synergizes with Ageing and Low-Grade Inflammation to Promote Gut and Peripheral Immune Cell Activation that Precede Nigrostriatal Degeneration
By onBackground Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of familial Parkinson’s disease (PD). The incomplete penetrance of LRRK2 mutations suggest that additional hits are required for disease onset. We hypothesized that chronic low-grade inflammation interacts with LRRK2 G2019S, the most frequent PD-associated mutation, to activate peripheral and central immune reactions and drive age-dependent neurodegeneration. Methods and Results We exposed wild-type and LRRK2 G2019S mice to a low chronic dose of lipopolysaccharide, and we performed a longitudinal analysis of central and peripheral immune reactions and neurodegeneration. Low-dose inflammation triggered nigrostriatal degeneration, macrophage/monocyte brain infiltration, and astro-/microgliosis. LRRK2 G2019S mice showed an early dysregulation of peripheral cytokines, increased CD4+ T-cell infiltration and α-synuclein aggregation in the colon. Interestingly, peripheral immune activation and colonic α-synuclein aggregation precede astro-/microgliosis and neurodegeneration. Conclusions Our study suggests an early role of the peripheral immune system and the gut in LRRK2 PD and provides a novel model to study early therapeutic immune targets and biomarkers.
