Stargardt disease is the most common inherited juvenile macular degeneration and is caused by mutations in the ABCA4 gene, leading to progressive retinal pigment epithelium (RPE) and photoreceptor loss. Emerging evidence suggests lysosomal impairment driven by bisretinoid accumulation and lysosomal membrane destabilization may contribute to degeneration. However, the relationship between lysosomal damage and inflammatory signaling in RPE cells remains poorly understood. Prior work from our lab in STGD1 iPSC-derived RPE demonstrates endolysosomal dysfunction, including altered phosphatidylethanolamine (PE) distribution at 3 months, increased PE and lyso-PE at 7 months, and reduced LC3 staining with impaired outer segment degradation. Our lab also found a trend toward increased IL-1β levels in 3-month Abca4−/− mouse RPE/eyecups. This study investigates whether STGD1 iPSC-derived RPE exhibits increased NLRP3 inflammasome activation and whether this correlates with lysosomal membrane permeabilization(LMP). We hypothesize that STGD1 RPE exhibits increased LMP and inflammasome activation compared to controls. LMP will be quantified by Galectin-3 puncta using confocal microscopy and ImageJ analysis, and inflammasome activation will be assessed by IL-1β secretion via ELISA. Immunoblotting will assess caspase-1 activation and IL-1β levels in 6-month Abca4−/− mouse eye cups as a disease-relevant model. This work aims to clarify inflammatory mechanisms in Stargardt disease and identify intervention points to prevent RPE degeneration.

Spinocerebellar ataxia 4 (SCA4) is a neurodegenerative disorder marked by gait and limb ataxia, dysarthria, and neuropathy. It is caused by a GGC repeat expansion in ZFHX3 (>40 repeats) and linked to a founder effect originating in Sweden. Detecting the expansion using common genetic testing methods, such as polymerase chain reaction (PCR), is challenging as the region is highly GC-rich and thermodynamically stable. This also prevents accurate resolution by the short-read next-generation sequencing commonly used for genetic testing. Long-read sequencing can resolve pathogenic repeat lengths but is relatively low throughput and use is limited by cost and access to the technology. PCR-based methods attempting to target this region have used commercial PCR kits designed to improve GC-rich amplification, but reliance on these specialized reagents leads to high per-sample costs and limits scalability for large cohorts. To address this, we developed a novel high-throughput PCR assay to screen a large U.S.-based undiagnosed ataxia cohort of 687 patients. GGC repeats in ZFHX3 were PCR-amplified, sized by fragment analysis, and expanded repeats were confirmed using nanopore long-read sequencing. Pathogenic expansions (51-74 repeats) were identified in three multigenerational families of Swedish ancestry presenting with cerebellar ataxia and sensory and/or autonomic neuropathy. SCA4 should be considered in undiagnosed ataxia patients of Swedish ancestry and this method will facilitate cost-effective high-throughput testing.

Trunk instability is one of the most debilitating consequences of spinal cord injury (SCI), increasing fall risk and severely limiting independence. Yet no reliable quantitative tool exists to characterize how injury level and severity specifically impair trunk control, a critical gap that hinders the development of targeted rehabilitation. This study introduces a three-dimensional motion capture system combined with a machine learning analytical pipeline to objectively assess seated trunk function in 18 chronic SCI patients (injury levels C3–L2; ASIA grades A–D) and 7 uninjured controls. Participants performed five seated trunk tasks while kinematics and concurrent electromyography (EMG) were recorded from bilateral core muscle groups. A machine learning pipeline incorporating random forest, SVM, and KNN algorithms is being applied to identify kinematic features most predictive of injury severity and location. Preliminary results show that success rates, shoulder displacement, and EMG activation patterns decline systematically with greater injury severity. As analysis continues, we aim to build a model that can predict how trunk function will be affected based on the nature and severity of a patient's injury. Ultimately, this work offers a novel and holistic way to quantify trunk dysfunction in SCI. One with real potential to improve fall risk assessment, guide rehabilitation, and help clinicians design treatment programs tailored to each patient's specific needs.

Down syndrome (DS) resulting from trisomy 21 (Ts21) is the most common genetic cause of intellectual disability, characterized by cognitive and learning deficits. However, the molecular and cellular mechanisms underlying altered cortical development in DS remain poorly understood. Prior work from our laboratory using single-nucleus multi-omics in developing Ts21 neocortex identified significant changes in the proportion of neural progenitors and deep/upper layer neurons as well as transcriptomic changes suggesting increased neurogenic asymmetric division. To validate these findings using an orthologous approach, we turned to primary human neural progenitor cells (phNPCs) and organoids, in vitro culture systems used to model neurogenesis. PhNPCs derived from Ts21, showed increased neurogenesis as compared to controls, consistent with accelerated neurogenesis. Similarly, cortical organoids derived from Ts21 hiPSCs displayed alterations in neural rosette size, number, and quality consistent with decreased progenitor proliferation, as well as altered molecular markers. Altogether our work aims to build on previous in vivo findings by using a human-relevant in vitro models to explore how Down syndrome impacts early cortical development at both the molecular and cellular levels, with the potential to guide future therapeutic approaches or biomarker identification.