Parkinson’s disease modeling in regenerative spiny mice (Acomys dimidiatus) captures key disease-relevant behavioral, histological, and molecular signatures
By onThis paper models PD for the first time in a unique regenerative mammalian model, spiny mice, finding that 6-OHDA and αSyn PFFs induce robust pathology.
Extracellular space diffusion modelling identifies distinct functional advantages of archetypical glutamatergic and GABAergic synapse geometries
By onWe modelled extracellular diffusion in super-resolved images of live brain tissue neuropil. We found that extracellular space geometry shapes local diffusion and this has functional implications for signaling arising from synaptic spill-over.
A framework for efficient CRISPRi-mediated silencing of retrotransposons in human pluripotent stem cells
By onThis methods paper outlines silencing transposable elements in hiPSCs using CRISPRi. Describes gRNA design, validation via multiome approach. Enables functional studies on TE transcription in hiPSC models.
Proteome Landscapes Decode Organelle Vulnerabilities in cortical and dopaminergic-like induced neurons Across Lysosomal Storage Disorders
By onLysosomal Storage Disorders impact lysosomal function and can be linked to Parkinson's Disease risk. LSD mutant cells show varied endolysosomal proteomes, with specific disruptions in neuronal cells.
Structural remodeling of the mitochondrial protein biogenesis machinery under proteostatic stress
By onCryo-ET showed protein aggregates, altered cristae, and reduced ribosome complexes in stressed mitochondria. Mitochondrial Hsp60 undergoes conformational changes to aid in protein folding, shedding light on mitochondrial proteostasis mechanisms.
Sex-dimorphic effects of neuromelanin buildup in rodent nigral dopamine neurons: implications for sex-biased vulnerability in Parkinson’s disease
By onNeuromelanin (NM) is pigment accumulating with age in human SNpc dopamine (DA) neurons. This study discloses unrealized NM effects within nigral DA neurons, advancing our comprehension of sex-specific features shaping sex-biased vulnerability to PD.
Introducing PIGMO, a novel PIGmented MOuse model of Parkinson’s disease
By onThere is a pressing need for the development of animal models of PD that properly mimic the its cardinal features. Here an AAV engineered to bypass the blood-brain barrier and coding for the human tyrosinase gene is used to generate the PIGMO model.
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.
