Allison Ann Dilliott

Currently, pathological inclusions of ubiquitinated TDP-43 are considered central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, this view has yielded sparse attention to covert alternative pathways of aggregation in the disease. Here, we identified a pathological axis independent of TDP-43 led by ARPP21, a SUZ domain-containing RNA-binding protein encoded by a gene recently described in strong association with ALS. ARPP21 showed large fibrillar non-ubiquitinated aggregates in all the non-SOD1 ALS cases studied, consistently segregating from TDP-43 pathology. Biophysically, ARPP21 undergoes spontaneous phase separation, with a higher propensity for condensate formation than TDP-43 but without co-aggregating with it. ARPP21 also exhibited very slow soluble behavior and lower condensate dynamics compared to TDP-43, an effect that was more pronounced for the ARPP21-P529L disease-related variant. In human iPSC-derived motor neurons, expression of ARPP21 variants was sufficient to drive condensate formation and reduce cell viability. Mechanistically, ARPP21 promoted intercellular propagation by inducing tunnelling nanotube formation, enabling efficient cell-to-cell spreading of aggregates. Genetic analyses further identified multiple ARPP21 variants in ALS, supporting its clinical relevance. Together, our findings uncover ARPP21 as a previously unrecognized TDP-43-independent aggregation pathway in ALS, with implications for disease heterogeneity and therapeutic targeting.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective degeneration of motor neurons with a substantial genetic contribution to disease risk. Distinct genetic etiologies converge on key pathogenic processes in ALS, including aberrant RNA metabolism, proteostatic stress, dysregulated vesicular transport, and mitochondrial dysfunction. Here, we investigate whether perturbed transcriptional programs associated with definitive ALS genes harbor elusive genetic contributors to disease. We analyzed RNA sequencing data profiling induced pluripotent stem cell-derived motor neurons from individuals with ALS ( N = 438) and controls ( N = 187). Leveraging an integrative analytical framework, we identified transcriptional pathways linking variants in definitive ALS genes to widespread coordinated co-expression activity driven by gene-specific transcriptional programs. We subsequently subjected all genes comprising significant pathways to genetic analyses to uncover novel targets and characterized these genes using single-nuclei transcriptomics of the motor and prefrontal cortices of individuals with ALS and controls. The identified transcriptional programs associated with definitive ALS genes showed strong concordance to established biology, including dysregulated proteostasis and mitochondrial stress in SOD1 ALS, protein aggregation and degradation pathways in FUS ALS, and altered vesicle dynamics, synaptic transmission, autophagy, and trafficking programs in GRN ALS. These pathways encompassed both well-established ALS genes, as well as six target genes— PTPRN2 , UNC13C , TTC3 , USP10 , PSMD4 , and RUFY3 —of which USP10 , PSMD4, and RUFY3 have not yet been described in the context of ALS genetic association studies. Single-nuclei analyses demonstrated that target gene expression was enriched in the baseline architecture of neuronal populations, supporting neuron-intrinsic mechanisms of vulnerability. PSMD4 showed region-specific dysregulation in selectively vulnerable Layer 5 motor neurons of individuals with ALS, implicating regionally divergent proteasome activation as a neuron-intrinsic feature of ALS vulnerability. Collectively, this work advances the molecular understanding of distinct genetic ALS etiologies, provides mechanistic insight into emerging ALS target genes, and establishes a generalizable framework that is readily applicable across heritable diseases for the identification of disease-relevant molecular pathways and target genes.

Pathogenic variants in leucine-rich repeat kinase 2 ( LRRK2 ) ¹ are among the most frequent monogenic causes of Parkinson’s disease (PD) ² and act through a gain-of-function mechanism of increased kinase activity. LRRK2 -targeted therapies are in clinical development, but interpretation of the rapidly expanding catalogue of rare LRRK2 variants remains a barrier to translation. Here, we present functionally annotated data on >350 LRRK2 coding variants using a standardized cellular assay with Rab10 phosphorylation as a readout of kinase activity and integrated these data with curated genetic and clinical annotations from the Movement Disorders Society Genetic Mutation Database (MDSGene). Variants differed in activation magnitude, ranging from modest increases (e.g., p.G2019S) to strongly activating substitutions such as p.Y1699C or p.L1795F. Activating variants occurred across the full length of LRRK2, although the largest effects clustered within the ROC–COR regulatory hub, where structural analysis identified subdomains forming an allosteric scaffold controlling kinase output. All known/established pathogenic variants showed increased activity, whereas benign and likely benign variants remained within the wild-type range. Functional effect sizes correlated with pathway activation in patient-derived immune cells, altogether providing a framework for ACMG-based variant interpretation in which kinase activation can support PS3 functional evidence for reclassification of variants.

Expanded short tandem repeats contribute to a broad spectrum of neurodegenerative diseases, yet their roles in Parkinson’s disease (PD) and parkinsonism remain incompletely characterized, especially across diverse ancestries. We analyzed short-read whole-genome (WGS) and clinical exome sequencing (CES) data from 38,365 individuals (28,861 WGS; 9,504 CES), encompassing 23,242 patients with PD, 4,729 patients with atypical parkinsonism and 10,394 healthy controls from 11 genetic ancestries. To determine carrier frequencies and characterize repeat structures across diverse ancestries, we genotyped 12 established pathogenic loci where normal, intermediate, and pathogenic alleles can be reliably differentiated using short-read sequencing data. Additionally, we conducted threshold-based associations to determine the minimum threshold associated with increased PD risk in 15,995 individuals (8,591 PD, 7,404 controls) of European ancestry. Pathogenic repeat expansions were detected in 62 patients (56 PD and 6 atypical parkinsonism) and 5 controls across seven loci ( AR , ATXN1 , ATXN2 , ATXN3 , CACNA1A , HTT and THAP11 ), spanning seven ancestries. Among these, ATXN2 expansions were the most frequently observed in PD and were present in African, East Asian, European and Middle Eastern ancestries. Additionally, intermediate ATXN2 repeat expansions exhibited a strong, length-dependent association with PD risk in the European population, with individuals with ≥32 repeats having a more than four-fold increased risk (odds ratio 4.25, 95% confidence interval 1.80-12.05). Overall, >92% of expanded alleles harbor CAA interruptions within the CAG tract. Pathogenic expansions at other loci, such as ATXN3 and THAP11 , showed more ancestry-specific distributions. Clinically, individuals with pathogenic ATXN2 and ATXN3 expansions most often presented with typical PD features but frequently showed earlier disease onset and a strong family history of PD. This large-scale, multi-ancestry study comprehensively maps the genetic landscape of pathogenic and intermediate repeat expansions in PD. Our findings confirm a length- and structure-dependent risk association for ATXN2 with PD in the European population and highlight the pleiotropic effects of repeat expansions across the parkinsonian spectrum.

Introduction: Variants in the polymerase gamma ( POLG) gene are associated with a wide range of mitochondrial disorders. Emerging evidence suggests a potential link between POLG variants and Parkinson’s disease (PD); yet, results remain inconclusive. Objectives: To investigate the genetic spectrum and prevalence of POLG variants in PD across diverse ancestries. Methods: We leveraged multi-ancestry genetic data from the Global Parkinson’s Genetics Program (GP2), including genotyping data from 98,589 and short-read sequencing data from 36,022 individuals. We performed a POLG rare variant screen, case-control association, and gene-level burden analyses. Results: Five PD cases carried potentially biallelic rare pathogenic/likely pathogenic POLG variants. Additionally, 228 individuals (POLG variant burden or common POLG variant enrichment and PD. Conclusions: POLG variants are overall rare in PD. The identification of rare pathogenic variants among PD cases suggests that POLG -related mitochondrial dysfunction may contribute to PD in isolated instances, particularly under recessive inheritance. Our findings support a role for POLG variants in select cases and underscore the need for larger-scale sequencing and functional studies.

Background: PD GENEration ( NCT04057794 , NCT04994015 ), sponsored by the Parkinson’s Foundation in partnership with Aligning Science Across Parkinson’s (ASAP) through the Global Parkinson’s Genetics Program (GP2), is an international, observational, clinical research study that offers genetic testing and counseling to people living with Parkinson’s disease (PwP) at no cost. PD GENEration has aimed to empower PwP and their clinicians with knowledge of their genetic status, to accelerate recruitment into precision medicine trials, and to advance research through data sharing. Since its launch in 2019, the study has expanded to enroll over 32,000 PwP (as of March 31, 2026), from 10 countries across North, Central, and South America, the Caribbean, and Israel. Methods: Over the course of 6 years, PD GENEration has evolved to accommodate the growing scientific and research needs of the Parkinson’s community while also increasing the ability to return genetic test results to PwP at a greater scale. Participants with a diagnosis of Parkinson’s disease (PD) may enroll in-person or virtually where informed consent and blood sample collection can occur. Samples are analyzed at a College of American Pathologists/Clinical Laboratory Improvement Amendments (CAP/CLIA)-certified laboratory using whole genome sequencing, with variants curated for a primary panel of seven PD-associated genes. Results are disclosed during a genetic counseling visit, where further testing is offered for two optional additional gene panels. Those who consent undergo analysis of additional genes, and results are returned during a genetic counseling visit for those that test positive for a variant. In addition to returning genetic results to PwP, a central pillar of the study design has been the open sharing of genomic data to advance discovery in PD research in partnership with ASAP and GP2. Discussion: PD GENEration applies a flexible framework, allowing for country specific considerations and the integration of multiple site models, evolving based on participant needs and the prioritization of equity and accessibility. We summarize PD GENEration’s implementation and scaling, highlight key accomplishments and lessons learned, and provide guidance for those interested in implementing large-scale clinical genetic testing studies across other diseases and therapeutic domains.

Background: Large‐scale sequencing initiatives have generated extensive genomic resources essential for variant interpretation, yet their effective use often requires bioinformatics expertise. To support identification of Parkinson's disease (PD) risk and disease‐causing variants, we developed an open‐access, summary‐level genomic data browser. Methods: We performed uniform joint variant calling to harmonize whole‐genome sequencing (WGS) data from AMP‐PD Release 4, GP2 Data Releases, and additional controls from the Alzheimer's Disease Sequencing Project. Clinical‐exome sequencing (CES) data from GP2 Release 8 were also included. Results: The integrated dataset included 31,665 WGS and 9,559 CES samples, spanning 11 ancestries and over 300 million variants. Conclusions: The GP2 Genome Browser is a lightweight, flexible platform providing intuitive gene‐ and variant‐level summaries with ancestry‐stratified allele frequencies and functional annotations. It is open source and freely accessible at https://gp2.broadinstitute.org , enabling broad access to PD genomic data and supporting global research efforts. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: Essential tremor (ET) is a complex neurological disorder with a strong genetic basis, yet there remains a disparity between its estimated heritability and currently known genetic risk. This missing heritability has led to a lack of appropriate treatments and has exacerbated the misdiagnosis of patients. Methods: To address the missing heritability of ET, we called copy number variants (CNVs) in a large cohort of ET patients (n = 1,853) and unaffected controls (n = 10,336). CNVs were called from single nucleotide polymorphism (SNP) microarray data using PennCNV and QuantiSNP and only rare CNVs (frequency < 1%) intersecting protein coding regions of the genome were analyzed. To investigate whether CNV occurrence was associated with ET, global burden, pathogenicity burden, gene set enrichment, and gene burden tests were conducted. Results: Global duplication burden by CNV number, CNV length, and number of genes affected by CNVs were all significantly elevated in ET patients compared to controls. Across gene-sets, duplications affecting Mendeliome genes, genes highly expressed in the brain, and genes expressed in the cerebellum were significantly enriched in patients compared to controls. Gene-based burden testing indicated that duplications involving ZNF813 were significantly less frequent in ET patients than in controls. No associations with deletion events were observed. Discussion: Our results point to rare copy number duplications affecting protein coding regions of the genome as likely contributors to ET genetic risk. However, specific susceptibility genes could not be reliably identified, highlighting the need for larger studies of diverse variant types to clarify the genetic architecture of ET.

ATXN2 expansions of ≥33 CAG-repeats are associated with spinocerebellar ataxia type 2, while intermediate length expansions have been associated with amyotrophic lateral sclerosis (ALS). Yet, no consensus is established regarding the lengths that define a true association with ALS risk, with recent studies debating between a lower limit of ≥29 or ≥31 repeats. Here, we assessed the risk of ALS imparted by various ATXN2 repeat lengths to establish an accepted lower limit of repeats that impart risk of disease in the largest meta-analysis to-date. We identified 19 studies with carrier counts of expansions ranging from 24 to ≥34 repeats in cohorts of individuals with ALS and controls that we meta-analysed with the ATXN2 repeat lengths of the large-scale Project MinE ALS Consortium dataset (total individuals with ALS = 19202; total controls = 22177) and determined a lower limit of 30 repeats defining significant ALS risk. These findings were validated with a secondary assessment of the individuals with ALS captured within the meta-analysis using the gnomAD short tandem repeat dataset as a proxy control cohort. We also applied our defined ATXN2 repeat risk threshold to explore relationships with ALS clinical outcomes. While we did not observe a significant relationship between ATXN2 repeat lengths and age of ALS onset, we did identify a significant inverse correlation between ATXN2 repeat lengths as a continuous metric and duration of disease and found that individuals with ALS carrying the risk variant allele of ≥30 repeats had significantly shorter times to diagnosis than those without the repeat expansion. Our comprehensive analyses propose a lower-limit threshold of ≥30 ATXN2 trinucleotide repeats in length defining true ALS risk. These findings are imperative for allowing improved accuracy in risk interpretation and guidance for patients and their families, particularly as clinical genetic testing efforts continue to expand and there becomes increased need for guiding targeted clinical trial inclusion criteria. Our results may also aid in future analyses assessing ATXN2 pathogenic mechanisms and therapeutic strategies.

Background: Large-scale sequencing initiatives have generated extensive genomic resources essential for variant interpretation, yet their effective use often requires bioinformatics expertise. To support identification of Parkinson’s disease (PD) risk and disease-causing variants, we developed an open-access, summary-level genomic data browser. Methods: We performed uniform joint variant calling to harmonize whole-genome sequencing (WGS) data from AMP-PD Release 4, GP2 Data Releases, and additional controls from the Alzheimer’s Disease Sequencing Project. Clinical exome sequencing (CES) data from GP2 Release 8 was also included. Results: The integrated dataset includes 31,665 WGS and 9,559 CES samples, spanning eleven ancestries and over 300 million variants. Conclusion: The GP2 Genome Browser is a lightweight, flexible platform providing intuitive gene- and variant-level summaries with ancestry-stratified allele frequencies and functional annotations. It is open source and freely accessible at https://gp2.broadinstitute.org , enabling broad access to PD genomic data and supporting global research efforts.