Pedro Chana-Cuevas

Background: Parkinson’s disease (PD), the most common neurodegenerative movement disorder, is commonly thought of as an aging and sporadic disease; however, 5-14% of individuals experience disease onset before the age of 50 years (early-onset PD; EOPD) and about 20% have a positive family history. In the case of both EOPD and people with a family history of PD, evidence suggests higher rates of a disease-causing genetic contribution. Objectives: Our goal was to perform a variant screening of seven PD-related genes and 21 genes associated with related parkinsonian disorders to identify pathogenic/likely pathogenic variants and variants of uncertain significance within EOPD and family-history-positive individuals within the Latin American Research Consortium on the Genetics of PD (LARGE-PD). Methods: We performed short-read whole-genome sequencing on a subset of 263 individuals with EOPD and/or a familial history of PD who had no known pathogenic PD variant in genotyping data. Results: Of the analyzed individuals, a monogenic burden in primary and secondary PD genes due to pathogenic or likely pathogenic variants for PD was observed in 4.7%, an additional 5.5% had pathogenic or likely pathogenic variants for Gaucher’s disease, and 2.7% had known risk variants in GBA1 . Conclusions: By expanding the reported spectrum of disease-associated variants in a Latin American population, we identified previously unreported or underrepresented variants that would likely be missed by array-based or targeted screening approaches and contribute to the characterization of EOPD and familial PD in Latin America.

The genetics of Parkinson’s disease (PD) in underrepresented populations remain poorly characterized, potentially overlooking population-specific contributions. We analyzed 461 Chilean PD cases from a movement disorders center. Pathogenic, likely pathogenic, or GBA1 risk variants were identified in 58 individuals (12.6%), mainly in LRRK2 (50%) and GBA1 (44.8%), while PRKN, SNCA , and SQSTM1 collectively represented 5.2%. All LRRK2 variants were p.G2019S, with an overall frequency of 6.3%, the highest reported in South America, and enrichment of Ashkenazi Jewish ancestry at this locus. These findings characterize the genetic landscape of PD in Chile and support its relevance for LRRK2 -targeted studies.

Background: Evidence on environmental determinants of Parkinson’s disease (PD) in Latin America is limited and their attributable burden remains poorly defined in the region. We examined associations between environmental exposures and PD and quantified their contribution to disease burden.Methods: We analyzed 9887 participants from nine Latin American countries in a case control study. Associations between environmental exposures and PD were estimated using logistic regression adjusted for age, sex, and country. Population attributable fractions (PAFs) were calculated for positively associated exposures, defined as severe head trauma or at least 5 years of exposure for other risk factors.Findings: Weekly caffeine consumption and tobacco use for at least 5 years were inversely associated with PD (adjusted OR [aOR] 0·77, p < 0·0001; aOR 0·83, p = 0·0009). Severe head trauma (aOR 1·35, p < 0·0001), occupational pesticide exposure (aOR 1·42, p = 0·0003), occupational metal exposure (aOR 1·29, p = 0·0299), rural living (aOR 1·60, p < 0·0001), and well water consumption (aOR 1·22, p = 0·0014) were positively associated with PD. Dose related associations were observed for caffeine, tobacco, occupational pesticides and metals, rural living, and well water consumption. The joint PAF across five risk exposures was 13·7% (95% CI 9·8 to 17·3), with higher estimates in El Salvador, Brazil, Colombia, males, and participants younger than 60 years. Sensitivity and lag analyses were directionally consistent.Interpretation: Selected environmental exposures may account for a meaningful proportion of PD burden in Latin America, supporting further research and public health attention to environmental determinants in the region.

Background: Although levodopa is the gold standard treatment for Parkinson's disease (PD), its chronic use is associated with levodopa-induced dyskinesia (LID), a motor complication that impacts prognosis, quality of life, and treatment costs. Most known LID-associated factors have been identified in European-descendant populations. Objectives: To describe the epidemiology of LID in Latin American and Caribbean (LATAM) countries and assess the relevance of known and novel LID-associated factors in this population. Methods: We conducted a cross-sectional study using data from the Latin American Research consortium on the Genetics of Parkinson's Disease (LARGE-PD). We included PD patients with information on LID status and levodopa use from eight LATAM countries. LID prevalence was calculated overall and by country. Countries were compared on demographic and clinical variables. Logistic regression was used to identify associations with LID. Results: A total of 3695 PD patients (58.8% male) were included. Overall LID prevalence was 25.4% [95% CI: 24.06–26.87], ranging from 9.3% in Colombia to 45.1% in Puerto Rico. Prevalence increased progressively with longer disease duration. Country comparisons showed that not all known LID-associated factors explained prevalence differences. In logistic regression, fast disease progression was significantly associated with LID (OR: 1.55, 95%CI: 1.16–2.07), while sex was not (OR: 1.02, 95%CI: 0.87–1.18). Conclusions: This is the largest study on LID epidemiology in LATAM. While some known risk factors remain relevant, others, like sex, do not, underscoring the need for population-specific studies. Future work should integrate environmental, clinical, and genetic data to better understand LID mechanisms.

Idiopathic Parkinson’s disease (iPD) represents the most prevalent form of Parkinson’s disease; however, the molecular mechanisms underlying its development remain only partially understood. N6-methyladenosine (m6A), the most abundant internal RNA modification in eukaryotic mRNA, has emerged as a key regulator of gene expression and has been implicated in neurodegenerative disorders. In this study, we performed integrated differential expression, weighted gene co-expression network analysis (WGCNA), and differential co-expression (DECO) analyses using peripheral blood RNA-seq data from Latin American controls and early iPD patients to investigate m6A-associated transcriptional alterations. WGCNA and differential expression analyses identified 1207 hub genes and 237 differentially expressed genes, respectively. The integration of these datasets with curated m6A-related genes yielded 12 overlapping candidate genes associated with early iPD. Subsequent DECO analysis revealed three significant m6A regulator–target differential co-expression links involving the m6A factors VIRMA, YTHDF3, and HNRNPA2B1. Experimental validation in an independent exploratory cohort confirmed altered expression of these regulators and increased m6A enrichment of NRCAM and PKHD1 transcripts. To our knowledge, this study represents the first integrative transcriptomic evaluation of m6A-associated regulatory patterns in early iPD within a Latin American population. Collectively, our findings suggest that selective m6A-associated transcriptional network alterations may contribute to the systemic molecular signatures observed in early iPD, warranting further validation in larger and mechanistically oriented studies.

The p97 protein is a member of the AAA+ family of ATPases. This protein is encoded by the VCP gene. It is a mechanoenzyme that uses energy from ATP hydrolysis to promote protein unfolding and segregation actively. The unfolded products are subsequently presented to the 26S proteasome for degradation. p97 substrate recognition is mediated by adaptors, which interact with substrates directly or indirectly through ubiquitin modifications, resulting in substrate funnelling into the central pore of the p97 hexamer and unfolding. Here, we engineered synthetic adaptors to target specific substrates to p97, using the extraordinary intracellular binding capabilities of camelid nanobodies fused to the UBX domain of the p97 adaptor protein Fas-associated factor-1 (FAF1). In such a way, we created a p97-directed proteolysis-targeting chimera (PROTAC), representing a novel and unique E3 ubiquitin ligase-independent strategy to promote specific proteolysis. All functional assays were performed in human cell lines to evaluate the system’s efficacy and specificity in a physiologically relevant context.

Background: Although levodopa remains the gold standard treatment for Parkinson’s disease (PD), its chronic use is associated with levodopa-induced dyskinesia (LID), a motor complication that impacts prognosis, quality of life, and treatment costs. Most known LID-associated factors have been identified in European-descendant populations. Objectives: To describe the epidemiology of LID in Latin American and Caribbean (LATAM) countries and assess the relevance of known and novel LID-associated factors in this population. Methods: We conducted a cross-sectional study using data from the Latin American Research consortium on the Genetics of Parkinson’s Disease (LARGE-PD). We included PD patients with information on LID status and levodopa use from eight LATAM countries. LID prevalence was calculated overall and by country. Countries were compared on demographic and clinical variables. Logistic regression was used to identify associations with LID. Results: A total of 3,695 PD patients (58.8% male) were included. Overall LID prevalence was 25.4% [95% CI: 24.06–26.87], ranging from 9.3% in Colombia to 45.1% in Puerto Rico. Prevalence increased progressively with longer disease duration. Country comparisons showed that not all known LID-associated factors explained prevalence differences. In logistic regression, fast disease progression was significantly associated with LID (OR: 1.55, 95%CI: 1.16–2.07), while sex was not (OR: 1.02, 95%CI: 0.87–1.18). Conclusions: This is the largest study on LID epidemiology in LATAM. While some known risk factors remain relevant, others, like sex, do not, underscoring the need for population-specific studies. Future work should integrate environmental, clinical, and genetic data to better understand LID mechanisms.

Background: Cognitive symptoms are highly prevalent in Parkinson's disease (PD), often manifesting as mild cognitive impairment (MCI). Yet, their detection and characterization remain suboptimal because standard approaches rely on subjective impressions derived from lengthy, univariate tests. Objective: We examined whether digital analysis of verbal fluency predicts cognitive status in PD. Methods: We asked 464 Spanish speakers with PD to complete taxonomic (animal), thematic (supermarket), and phonemic (/p/) fluency tasks. We quantified six response properties: semantic variability, granularity, concreteness, length, frequency, and phonological neighborhood. In Study 1, these properties were fed to a ridge regressor to predict Mattis Dementia Rating Scale (MDRS) scores and subscores. In Study 2, we used the same properties to compare (via a generalized linear model) and classify (via random forest) between 123 patients with and 124 without MCI. Results: In Study 1, predicted MDRS scores and subscores strongly correlated with actual ones, adjusting for clinical and cognitive variables ( R = 0.51, P < 0.001). In Study 2, MCI patients' words were less semantically variable, less concrete, and shorter, adjusting for clinical and cognitive variables ( P ‐values < 0.05). Machine learning discrimination between patients with and without MCI was robust in the validation set (area under the curve [AUC] = 0.76), with good generalization to unseen pre‐surgical (AUC = 0.68) and post‐surgical (AUC = 0.72) samples, surpassing MDRS scores (AUC = 0.54). Results were consistently driven by semantic variability, granularity, and concreteness. Conclusions: Digital word property analysis predicts cognitive symptom severity and distinguishes between cognitive phenotypes of PD, enabling scalable neuropsychological screenings. © 2025 International Parkinson and Movement Disorder Society.

Background: Hereditary ataxias are genetically diverse, yet up to 75% remain undiagnosed due to technological and financial barriers. A pathogenic ZFHX3 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. Variants were identified using PEPPER-Margin-DeepVariant 0.8 (SNVs), Sniffles 2.4 (SVs), and Vamos 2.1.3 (STRs). Ancestry was inferred using GenoTools with reference data from the 1000 Genomes Project, Human Genome Diversity Project, and an Ashkenazi Jewish panel. Haplotype analysis was conducted by phasing SNVs within ZFHX3 , and methylation profiling was performed with modbamtools. Results: We identified ZFHX3 GGC repeat expansions (47–55 repeats) in four individuals with progressive ataxia, polyneuropathy, and vermis atrophy. One case presented parkinsonism–ataxia, expanding the phenotype. Longer expansions correlated with earlier onset and greater severity. Hypermethylation was detected on the expanded allele, and haplotype analysis linked ultra-rare ZFHX3 variants to distant Swedish ancestry. Conclusion: This is the first report of SCA4 outside Northern Europe, confirming a shared founder haplotype and expansion instability. The presence of parkinsonism broadens the clinical spectrum. Comprehensive genetic testing across diverse populations is crucial, and long-read sequencing enhances diagnostic yield by detecting repeat expansions and SNVs in a single assay.

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease following Alzheimer's disease. Nearly 30 causative genes have been identified for PD and related disorders. However, most of these genes were identified in European‐derived families, and little is known about their role in Latin American populations. Objectives: Our goal was to assess the spectrum and frequency of pathogenic variants in known PD genes in familial PD patients from Latin America. Methods: We selected 335 PD patients with a family history of PD from the Latin American Research Consortium on the Genetics of PD. We capture‐sequenced the coding regions of 26 genes related to neurodegenerative parkinsonism. Of the 335 PD patients, 324 had sufficient sequencing coverage to be analyzed. Results: We identified pathogenic variants in 41 individuals (12.7%) in FBXO7 , GCH1 , LRRK2 , PARK7 , PINK1 , PLA2G6 , PRKN , SNCA , and TARDBP , GBA1 risk variants in 25 individuals (7.7%), and variants of uncertain significance in another 24 individuals (7.4%) in ATP13A2 , ATP1A3 , DNAJC13 , DNAJC6 , GBA1 , LRKK2 , PINK1 , VPS13C , and VPS35 . Of the 70 unique variants identified, 19 were more frequent in Latin Americans than in any other population. Conclusions: This is the first screening of known PD genes in a large cohort of patients with familial PD from Latin America. There were substantial differences in the spectrum of variants observed in comparison to previous findings from PD families of European origin. Our data provide further evidence that differences exist between the genetic architecture of PD in Latinos and European‐derived populations. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.