A molecular atlas of cell-type specific signatures in the parkinsonian striatum
By onProgressive dopamine loss in PD affects striatum cells differently. Transcriptomic analysis in mouse and human models reveals changes in neuronal and glial populations, highlighting resilient and vulnerable cell types for potential new treatments.
Leucine-rich repeat kinase 2 impairs the release sites of Parkinson’s disease vulnerable dopamine axons
By onSynaptic dysfunctions manifest early in Parkinson's disease. Research on LRRK2 mutations, using advanced genetic models, reveals their effects on neuronal synapses, primarily impacted by the disease, offering insights into potential early therapies.
Re-activation of neurogenic 2 niches in aging brain
By onWe developed a multimodal MERFISH platform to map cell fate in the brain, revealing quiescent neural stem cells in aged mice and humans. PTBP1 suppression reactivates them, driving neurogenesis and neuron integration with therapeutic potential.
Rapid LRRK2 Activation Induced by α-synuclein Preformed Fibrils Triggers Rab5 Phosphorylation and Dysregulates Endolysosomal Function, Gene Expression and Synaptic Activity in Neurons
By onα-Synuclein fibrils activate LRRK2 on early endosomes, disrupting Rab5 function and endolysosomal homeostasis in neurons, triggering chromatin changes and transcriptional reprogramming.
Single-nucleus multiomic profiling of the aging mouse substantia nigra reveals conserved gene alterations linked to Parkinson’s disease
By onSingle-nucleus analysis of mouse substantia nigra reveals cell-type-specific aging changes, highlighting PD-linked genes. Aging alters protein folding, myelination, and stress-response pathways, offering insights into PD risk.
Activation of transposable elements is linked to a region- and cell-type-specific interferon response in Parkinson’s disease
By onStudy explores transposable elements role in Parkinson's disease neuroinflammation. TE activation in specific brain regions correlates with innate immune responses, indicating potential involvement in chronic neuroinflammation and PD progression.
Elevated brain α-synuclein, phosphorylated-tau, and oxidative stress in mice that survived influenza A pneumonitis
By onInfluenza virus infection does not alter acute lung infection course in mice with Lrrk2 mutations. Surviving mice showed elevated neurodegeneration markers post-infection, suggesting a link between influenza and neurodegenerative diseases in humans.
Faecalibacterium prausnitzii, depleted in the Parkinson’s disease microbiome, improves motor deficits in α-synuclein overexpressing mice
By onTreatment with an 8-member consortium of bacteria depleted in PD patients, or the single member F. prausnitzii, improves motor and GI function and reduces αSyn aggregates in the brain of a mouse model of PD.
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
