Brain

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation is associated with a decline in human-specialized social-emotional and language functions. Most disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD targets brain regions that express genes containing human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroima...

The PTPN11 gene was recently described as a novel lesional epilepsy gene by extensive exome-wide sequencing studies. However, germline mutations of PTPN11 and other RAS-/MAP-Kinase signaling pathway genes cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11...

X-linked Dystonia-Parkinsonism (XDP) is a lethal adult-onset neurodegenerative disorder that exhibits features of dystonia and parkinsonism and is exclusively associated with a causal founder haplotype that is indigenous to the Philippines and affects Filipino males. Using patient-specific fibroblasts, neural stem cells (NSC), and other neuronal models, we discovered that cryptic alternative splicing caused by a novel SINE-VNTR-Alu (SVA) mobile element insertion into intron 32 of TAF1 is a mecha...

-synucleinopathies are severe neurodegenerative disorders characterized by intracellular aggregation of -synuclein, yet their molecular pathogenesis remains unknow. Here, we explore cell-specific changes in gene expression across different -synucleinopathies. We perform single-nucleus RNA sequencing (snRNA-seq) on nearly 300,000 nuclei from the prefrontal cortex of individuals with idiopathic Parkinsons disease (iPD), Parkinsons disease caused by LRRK2 mutations (LRRK2-PD), multiple system atrop...

Huntington disease (HD) is one of the most common repeat expansion disorders. Clinically, HD patients exhibit considerable visit-to-visit variability in symptoms and signs independent of measuring method or rater, yet neither the precise nature nor the determinants of this clinical variability are known. Leveraging detailed genetic and longitudinal clinical data from large cohorts of HD patients, this work 1) establishes within-individual variability in disease expression as an integral part of ...

Rapid-eye-movement (REM)-sleep behaviour disorder (RBD) can be a prodromal stage of -synucleinopathies, including Parkinsons disease (PD) and dementia with Lewy bodies (DLB), and provides a unique opportunity to study and understand early neurodegeneration. Previous research on RBD has identified common risk loci in several PD and DLB genes, but the full extent of its genetic architecture and disease-specific associations remain unknown. In the present study, we aimed to identify novel loci ass...

Genome-wide association studies of Parkinsons disease (PD) have identified multiple genetic variants across populations, but the biological mechanisms remain largely unknown. To investigate ancestry-specific disease pathways, we performed a series of Mendelian randomisation analyses, integrating GWAS results with ancestry-specific protein quantitative trait loci data. For Europeans, we utilised the UK Biobank plasma proteomics (UKB-PPP) dataset alongside a European PD GWAS. For East Asians, we c...

Dementia in Lewy body diseases (LBD) is common and arises through heterogeneous and incompletely understood pathways. Evidence suggests contributions from genetic factors, including APOE {varepsilon}4 genotype, co-pathology including concomitant Alzheimers disease pathology and hypoperfusion related to orthostatic hypotension. However, the relative impact of these factors remains unclear. To address this, we analysed 399 post-mortem brains from LBD cases comprising Parkinsons disease, Parkinsons...

Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a recently discovered histopathological lesion entity. Approximately half of affected individuals carry a pathogenic brain mosaicism in the X-linked SLC35A2 gene, and all suffer from epilepsy. In this work, we extended the search for genetic alterations of MOGHE by investigating sex chromosome copy number alterations in 29 brain tissue samples from 19 males and 10 females with histopathologically c...

BackgroundParkinsons disease (PD) remains incurable, with a long prediagnostic phase currently undetectable by existing methods. Identifying individuals at high risk of PD would enhance our understanding of the underlying pathophysiology and will open up new preventive or early therapeutic avenues. MethodsIn the largest proteomic study in neurodegenerative diseases to date, we analyzed blood samples from [~]74,000 individuals across discovery and validation cohorts. In the discovery phase, we l...

Lysosomal dysfunction is central to Parkinsons disease pathogenesis, with GBA1 as the strongest established genetic risk factor. Numerous other genes involved in lysosomal sphingolipid, glycosphingolipid and ceramide metabolism have been proposed as contributors to Parkinsons disease, underscoring the need for comprehensive genetic analyses across these pathways. We analysed rare variants (minor allele frequency < 0.01) across 36 lysosomal genes (excluding GBA1) in 8,267 individuals with Parkins...

Progressive supranuclear palsy (PSP) is a heterogeneous neurodegenerative disease characterised by the accumulation of misfolded 4-repeat tau within neurones and glial cells. There is limited longitudinal data on pathologically confirmed PSP patients with phenotypes other than classical Richardsons syndrome (RS), and the pathomechanisms responsible for the broad variability in clinical phenotype and progression are not well understood. An unresolved question in this context is whether distinct s...

BackgroundDespite its significant heritability, the genetic underpinnings of Parkinson disease (PD) remain incompletely understood, particularly the role of rare variants. Advances in population-scale sequencing now provide an unprecedented opportunity to uncover additional large-effect rare genetic risk factors and expand our understanding of disease mechanisms. MethodsWe leveraged whole-genome sequence data with linked electronic health records from 490,560 UK Biobank participants, identifyin...

Polygenic risk scores (PRS) in Parkinsons disease (PD) are associated with disease risk. Recently, pathway-specific PRS have been created to take advantage of annotations inking variants to biological pathways or cell types. Here, we investigated 8 biological pathways or regions of open chromatin using pathway-specific PRS: alpha-synuclein pathway, adaptive immunity, innate immunity, lysosomal pathway1, endocytic membrane-trafficking pathway, mitochondrial pathway, microglial open chromatin sing...

Lewy body (LB) diseases are an umbrella term encompassing a range of neurodegenerative conditions all characterized by the hallmark of intra-neuronal -synuclein associated with the development of motor and cognitive dysfunction. In this study, we have conducted a large meta-analysis of DNA methylation across multiple cortical brain regions, in relation to increasing burden of LB pathology. Utilizing a combined dataset of 1,217 samples across 844 unique donors, we identified a set of 24 false dis...

The genomic landscape of the Indian population, particularly for age-related disorders like Parkinsons disease (PD) remains underrepresented in global research. Genetic variability in PD has been studied predominantly in European populations, offering limited insights into its role within the Indian population. To address this gap, we conducted the first pan-India genomic survey of PD involving 4,806 cases and 6,364 controls, complemented by a meta-analysis integrating summary statistics from a ...

Parkinsons disease (PD) is a complex neurodegenerative disorder characterised by selective neuronal loss. We integrate deep full-length single-nuclei sequencing of the human substantia nigra with novel genome-wide association studies (GWAS) identifying genetic and cellular drivers of PD. Genetic risk converges on AGTR1+ dopaminergic neurons and perineuronal oligodendrocytes (pODCs), both reduced in PD, as well as oligodendrocyte precursor cells, enriched among disease-disrupted intercellular int...

Risk variants in multiple genes, including GBA1, strongly implicate lipid metabolism in Parkinsons disease (PD) onset and progression. We show that common PD risk variants at the serine palmitoyltransferase small subunit B (SPTSSB) locus, a key regulator of de novo sphingolipid biosynthesis, are associated with increased SPTSSB brain expression and elevated plasma ceramides. Additional analyses strongly support our hypothesis that a common SPTSSB causal variant is responsible for PD risk as well...

Ataxia-telangiectasia (A-T) is a rare genetic disease caused by mutations in the gene encoding the ATM (ataxia-telangiectasia mutated) protein. Although neuronal degeneration in the cerebellum remains the most prominent sign in A-T pathology, neuroimaging studies reveal myelin abnormalities as early comorbidities. We hypothesize that these myelin defects are the direct consequence of ATM deficiencies in the oligodendrocytes (OL) lineage. We examined samples from ten A-T brains in which the ATM m...

Parkinsons disease (PD) is a progressive neurodegenerative disorder with complex and heterogeneous molecular pathology across the brain. However, the full cellular architecture of PD progression remains unresolved. Here, we present a comprehensive single-nucleus transcriptomic atlas of PD spanning multiple anatomically and clinically relevant brain regions to capture shared and region-influenced transcriptomic features from 97 deeply phenotyped donors, including individuals across the full spect...