Although the presence of α-syn inclusions is a common hallmark of these disorders, the exact nature of the deposited protein is specific to each disease. They are characterised by stereotypical brain cell loss accompanied by the formation of proteinaceous aggregations of the protein α-synuclein (α-syn), being, therefore, termed α-synucleinopathies. Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy are neurodegenerative disorders resulting in progressive motor/cognitive deficits among other symptoms.
Our results identify LRP1 as a key regulator of tau spread in the brain, and therefore a potential target for the treatment of diseases that involve tau spread and aggregation. Furthermore, downregulation of LRP1 in an in vivo mouse model of tau spread was found to effectively reduce the propagation of tau between neurons. The interaction between tau and LRP1 is mediated by lysine residues in the microtubule-binding repeat region of tau. Knockdown of LRP1 significantly reduced tau uptake in H4 neuroglioma cells and in induced pluripotent stem cell-derived neurons. Here we show that the low-density lipoprotein receptor-related protein 1 (LRP1) controls the endocytosis of tau and its subsequent spread. However, although the propagation of tau has been extensively studied, the underlying cellular mechanisms remain poorly understood. This observation and complementary experimental studies3,4 have suggested that tau can spread in a prion-like manner, by passing to naive cells in which it templates misfolding and aggregation. Progression of these diseases is characterized by the sequential spread and deposition of protein aggregates in a predictable pattern that correlates with clinical severity². The microtubule-associated protein tau has a central role in the pathogenesis of several forms of dementia known as tauopathies-including Alzheimer’s disease, frontotemporal dementia and chronic traumatic encephalopathy¹. The spread of protein aggregates during disease progression is a common theme underlying many neurodegenerative diseases. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility. Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10⁻¹¹), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10⁻⁸) and WWOX (HR = 2.12, P = 2.37 × 10⁻⁸) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits.
RIDDLE SCHOOL TRANSFER PHREDS CODE DRIVER
General semantic classes have been excluded from the analysis (the entire enrichment is presented in Table S8).Ī key driver of patients’ well-being and clinical trials for Parkinson’s disease (PD) is the course that the disease takes over time (progression and prognosis). Gene ontology terms are filtered and grouped into semantic classes by semantic similarity. (D) Functional enrichment (for Gene Ontology biological processes) performed with the 50 nodes that are communal across the 3 networks. (C) Venn diagram detailing the overlaps across the nodes composing the experimental-Mendelian PD-sporadic PD networks. (B) Pink nodes are the seeds of the experimental network, whereas blue nodes are those that overlap across the experimental network and the protein interaction network built around the risk (sporadic) PD genes (Table S7). Pink nodes are the seeds of the experimental network, whereas green nodes are those that overlap across the experimental network and the protein-interaction network built around the PD Mendelian genes (Table S6). The network was built after downloading the (first layer) protein interactors of the seeds and by filtering for reproducibility of interactions. WPPINA confirms the functional relation between the 38 hits and known PD genes (A) The 34 seeds from the ''experiment'' (Table S8) have been used as seeds for building the ''Experimental protein-protein interactions network'' or hits network.
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