Long-read sequencing identifies repeat expansions in Parkinson's disease.

Pathogenic GAA repeat expansions in are an established cause of late-onset cerebellar ataxia, but have not been linked to Parkinson's disease (PD). Given emerging evidence that repeat expansions in ataxia-associated genes like , can contribute to atypical or familial forms of PD, we investigated whether expansions might play a similar role. Using long-read whole-genome sequencing on 411 individuals with PD and 197 neurologically healthy controls from the PPMI cohort, alongside 1,429 additional controls from the NIH CARD initiative, the 1000 Genomes Project, and the All of Us program, representing globally diverse populations.

Gut-brain nexus: Mapping multimodal links to neurodegeneration at biobank scale.

Alzheimer's disease (AD) and Parkinson's disease (PD) are influenced by genetic and environmental factors. We conducted a biobank-scale study to (i) identify endocrine, nutritional, metabolic, and digestive disorders with potential causal or temporal associations with AD/PD risk before diagnosis; (ii) assess plasma biomarkers' specificity for AD/PD in the context of co-occurring gut related traits and disorders; and (iii) integrate multimodal datasets to enhance AD/PD prediction. Our findings show that several disorders were associated with increased AD/PD risk before diagnosis, with variation in the strength and timing of associations across conditions.

Cerebellum mitochondrial DNA copy number is increased in Parkinson's disease.

Bioinformatics methods can be used to quantify mitochondrial DNA copy number from whole genome sequencing (WGS) data. We evaluated mitochondrial DNA copy number from human brain-derived WGS data using the fastMitoCalc tool. 341 Parkinson's Disease cerebellum samples were compared with 74 age-matched controls from the North American Brain Expression Consortium.

Tackling a disease on a global scale, the Global Parkinson's Genetics Program, GP2: A new generation of opportunities.

The need for more diversity in research is a widely recognized problem, especially in the genetics and genomics fields. While resolving this problem seems straightforward by recruiting and sequencing research participants from underrepresented populations, implementing an effort like this is complex operationally. Key considerations include ensuring equity, building capacity, and creating a sustainable research collective that works collaboratively to address local and global questions in research.

A CGG Repeat Expansion in CSNK1E Associated with Progressive Myoclonic Epilepsy with Incomplete Penetrance.

Background: Progressive myoclonic epilepsy is a heterogeneous neurodegenerative disorder characterized by early-onset myoclonus, epilepsy, generalized tonic-clonic seizures, and progressive neurological deterioration. Recently, a CGG repeat expansion and increased CSNK1E DNA methylation have been shown to be associated with developmental and epileptic encephalopathies.

Objective: To identify structural variants or repeat expansions associated with progressive myoclonic epilepsy in an Azerbaijani family using long-read sequencing.

Polygenic prediction of body mass index and obesity through the life course and across ancestries.

Polygenic scores (PGSs) for body mass index (BMI) may guide early prevention and targeted treatment of obesity. Using genetic data from up to 5.1 million people (4.

Haplotype-Resolved DNA Methylation at the Locus identifies Allele-Specific Epigenetic Signatures Relevant to Alzheimer's Disease Risk.

The gene encodes a key lipid transport protein and plays a central role in Alzheimer's disease (AD) pathogenesis. Three common alleles, ε2 (rs7412(C>T), ε3 (reference), and ε4 (rs429358(T>C)), arise from two coding variants in exon 4 and confer distinct AD risk profiles, with ε4 increasing risk and ε2 providing protection. The ε3-linked variant rs769455[T] has also been associated with elevated AD risk in individuals of African ancestry carrying both rs769455[T] and ε4 alleles.

Temporal dynamics of proteome and phosphorproteome during neuronal differentiation in the reference KOLF2.1J iPSC line.

Induced pluripotent stem cell (iPSC)-derived neurons have emerged as a powerful model to investigate both neuronal development and neurodegenerative diseases. Although transcriptomics and imaging have been applied to characterize neuronal development signatures, comprehensive datasets of protein and post-translational modifications (PTMs) are not readily available. Here, we applied quantitative proteomics and phosphoproteomics to profile the differentiation of the KOLF2.

Dissecting the biological impact of mutations using multi-omics in an isogenic setting.

is a risk gene for multiple neurodegenerative diseases, including Lewy Body Dementia and Parkinson's disease, and biallelic pathogenic variants in the gene result in the lysosomal storage disorder Gaucher disease. encodes the enzyme glucocerebrosidase (GCase), and alterations in the gene result in reduced enzymatic activity, which affects lysosome function downstream. Induced pluripotent stem cells (iPSCs) are a useful tool for testing the functional consequences of gene variants in an isogenic setting.

Large-scale HLA immunopeptidome and interactome profiling in microglia.

Microglia are immune cells of the brain and act as major antigen presenting cells. Antigen presentation involves the human leukocyte antigen (HLA) complex, which is implicated in genetic risk of multiple neurodegenerative diseases. How HLA affects the function of microglia in the context of neurodegenerative disease remains unclear.

Erratum: The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.

[This corrects the article DOI: 10.1212/NXG.0000000000200246.

Identification of GGC Repeat Expansions in ZFHX3 among Chilean Movement Disorder Patients.

Background: Hereditary ataxias are genetically diverse, yet up to 75% remain undiagnosed due to technological and financial barriers. The GGC repeat expansion in ZFHX3, responsible for spinocerebellar ataxia type 4 (SCA4), has only been described in individuals of Northern Europeandescent.

Objective: Uncover the genetic etiology of suspected hereditary movement disorders.

Genetic Contributions to Alzheimer's Disease and Frontotemporal Dementia in Admixed Latin American Populations.

Latin America's diverse genetic landscape provides a unique opportunity to study Alzheimer's disease (AD) and frontotemporal dementia (FTD). The Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat) recruited 2,162 participants with AD, FTD, or as healthy controls from six countries: Argentina, Brazil, Chile, Colombia, Mexico, and Peru. Participants underwent genomic sequencing and population structure analyses were conducted using Principal Component Analysis and ADMIXTURE.

stratified genome-wide association studies provide novel insights into the genetic etiology of Alzheimers's disease.

Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E gene () ε2/ε3/ε4 polymorphism remains the longstanding benchmark for genetic disease risk with a consistently large effect across studies. Despite this massive signal, the exact mechanisms for how ε4 increases and for how ε2 decreases dementia risk is not well-understood. Importantly, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in s4 carriers, hampering the treatment of those with the highest unmet need.

Identification of GGC Repeat Expansions in Among Chilean Movement Disorder Patients.

Background: Hereditary ataxias are genetically diverse, yet up to 75% remain undiagnosed due to technological and financial barriers. A pathogenic GGC repeat expansion was recently linked to spinocerebellar ataxia type 4 (SCA4), characterized by progressive ataxia and sensory neuropathy, with all reported cases in individuals of Northern European ancestry.

Methods: We performed Oxford Nanopore Technologies (ONT) genome long-read sequencing (>115 GB per sample) on a total of 15 individuals from Chile; 14 patients with suspected hereditary movement disorders and one unrelated family member.

Proteomic Analysis of Endemic Viral Infections in Neurons offers Insights into Neurodegenerative Diseases.

Endemic viral infections with low pathogenicity are often overlooked due to their mild symptoms, yet they can exert long-term effects on cellular function and contribute to disease pathogenesis. While viral infections have been implicated in neurodegenerative disorders, their impact on the neuronal proteome remains poorly understood. Here, we differentiated human induced pluripotent stem cells (KOLF2.

The LRRK2 p.L1795F variant causes Parkinson's disease in the European population.

LRRK2-PD represents the most common form of autosomal dominant Parkinson's disease. We identified the LRRK2 p.L1795F variant in three families and six additional unrelated cases using genetic data from over 50,000 individuals.

-associated parkinsonism with and without evidence of alpha-synuclein aggregates: longitudinal clinical and biomarker characterization.

Among -associated parkinsonism cases with nigral degeneration, over two-thirds demonstrate evidence of pathologic alpha-synuclein, but many do not. Understanding the clinical phenotype and underlying biology in such individuals is critical for therapeutic development. Our objective was to compare clinical and biomarker features, and rate of progression over 4 years of follow-up, among -associated parkinsonism cases with and without evidence of alpha-synuclein aggregates.

The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.

Although large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathologic mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across 10 different phenotypic groups, including neurologic conditions such as Alzheimer disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson disease.

CARDBiomedBench: A Benchmark for Evaluating Large Language Model Performance in Biomedical Research: A novel question-and-answer benchmark designed to assess Large Language Models' comprehension of biomedical research, piloted on Neurodegenerative Diseases.

Backgrounds: Biomedical research requires sophisticated understanding and reasoning across multiple specializations. While large language models (LLMs) show promise in scientific applications, their capability to safely and accurately support complex biomedical research remains uncertain.

Methods: We present , a novel question-and-answer benchmark for evaluating LLMs in biomedical research.

Large-scale genetic characterization of Parkinson's disease in the African and African admixed populations.

Elucidating the genetic contributions to Parkinson's disease (PD) etiology across diverse ancestries is a critical priority for the development of targeted therapies in a global context. We conducted the largest sequencing characterization of potentially disease-causing, protein-altering and splicing mutations in 710 cases and 11,827 controls from genetically predicted African or African admixed ancestries. We explored copy number variants (CNVs) and runs of homozygosity (ROHs) in prioritized early onset and familial cases.

African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in .

Recently, a novel African ancestry specific Parkinson's disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (). This variant (rs3115534-G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups, but is almost absent in European and Asian ancestry populations.

African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1.

Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant ( rs3115534 -G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups but is almost absent in European and Asian ancestry populations.

The ZFHX3 GGC Repeat Expansion Underlying Spinocerebellar Ataxia Type 4 has a Common Ancestral Founder.

Background: The identification of a heterozygous exonic GGC repeat expansion in ZFHX3 underlying spinocerebellar ataxia type 4 (SCA4) has solved a 25-year diagnostic conundrum. We used adaptive long-read sequencing to decipher the pathogenic expansion in the index Utah family and an unrelated family from Iowa of Swedish ancestry. Contemporaneous to our discovery, other groups identified the same repeat expansion in affected individuals from Utah, Sweden, and Germany, highlighting the current pivotal time for detection of novel repeat expansion disorders.