About

William C Mobley is a Clinical Associate Professor in the Department of Pharmaceutics at the University of Florida College of Pharmacy. He teaches courses such as Drug Delivery and Dosage Forms, Problem Solving, Integrated Case Studies, and Pharmaceutical Compounding. Prior to his faculty appointment at UF, he held academic positions at Idaho State University College of Pharmacy and Nova Southeastern University College of Pharmacy. His professional background includes experience as a retail pharmacist, which he credits for providing practical insight that he brings into his teaching. Mobley's teaching philosophy emphasizes motivating students to engage in effortful and meaningful learning by showing respect and concern, stimulating curiosity, and making learning activities relevant to real-world practice. His approach aims to help students construct understanding by integrating new knowledge with existing knowledge, fostering deeper and more durable learning. His accomplishments include receiving awards such as the Jean Lamberti Mentorship Award in 2022, the Florida Pharmacy Association Pharmaceutics Innovation and Teaching Excellence Award in 2022, and being named Teacher of the Year by the American Association of Colleges of Pharmacy in 2022. His research interests and contributions focus on optimizing pharmacy education, critical thinking, and problem-solving skills, with numerous publications and presentations in these areas.

Research topics

• Medicine
• Neuroscience
• Pathology
• Computer Science
• Biology
• Bioinformatics
• Genetics
• Psychology
• Artificial Intelligence
• Cell biology
• Immunology
• Data science
• Business
• Risk analysis (engineering)
• Internal medicine
• Engineering
• Social psychology
• Audiology

Selected publications

• Single-nucleus multiomic profiling of the aging mouse substantia nigra reveals conserved gene alterations linked to Parkinson's disease

  Genome Research · 2026-03-04

  preprintOpen access

  Parkinson's disease (PD) is a prevalent neurodegenerative disorder predominantly affecting individuals over 60. Its motor symptoms stem from the deterioration of dopaminergic neurons within the substantia nigra. Despite aging being a significant risk factor, the specific mechanisms linking aging and PD pathology remain unclear. Leveraging advancements in single-cell genomics, this study utilizes single-nucleus multiome sequencing to capture transcriptomic and epigenetic profiles from 40,125 cells across the lifespan of the mouse substantia nigra. Our analysis pinpoints age-associated changes at a cell type–specific level, revealing a subset of genes that increasingly express with age and are enriched in PD-related pathways, notably in oligodendrocytes at late aging stages. Integration with five public PD single-cell RNA-seq data sets highlights 85 genes consistently differentially expressed with aging and PD. Key genes such as Hsp90aa1 and Hsp90ab1 are upregulated at late aging stages in oligodendrocytes, microglia, and glutamatergic neurons. Additionally, Apoe in microglia and genes related to protein folding in oligodendrocytes are upregulated at late aging stages, whereas genes involved in myelination are downregulated at early aging stages in oligodendrocyte. Our multiomic atlas underscores the substantial regulatory network changes during aging that may predispose to PD, providing valuable insights for furthering understanding of PD pathogenesis and potential therapeutic targets.

  PublisherOA PDFDOI

• Preformed fibrils of α-synuclein rapidly activate LRRK2 on early endosomes, driving Rab5 phosphorylation and disrupting endolysosomal and synaptic function

  npj Parkinson s Disease · 2026-05-12

  articleOpen accessSenior author

  Parkinson's disease (PD) is characterized by α-synuclein aggregation and perturbation of the endolysosomal network (ELN), yet the molecular mechanisms linking α-synuclein pathology to neuronal dysfunction remain unclear. Here we report that treatment of mouse cortical neurons with α-synuclein preformed fibrils (PFFs) alters lysosomal composition and impairs lysosomal function, coupled with extensive chromatin remodeling and transcriptional reprogramming, including suppression of neuronal gene networks and activation of senescence-like programs. Mechanistically, these changes are associated with rapid recruitment and activation of the PD-associated kinase LRRK2 on early endosomes, where it phosphorylates Rab5, a key early endosomal GTPase, leading to remodeling of the Rab5 interactome, altered effector engagement, and endosomal dyshomeostasis. Pharmacological inhibition of LRRK2 with MLi-2 restores Rab5 activity, lysosomal function, chromatin accessibility, gene expression, and neuronal excitability. Knockdown of Rab5 partially rescues chromatin changes, supporting its role as a downstream effector. These findings identify LRRK2 hyperactivation and the LRRK2-Rab5 axis as key mediators of PFF-induced neuronal dysfunction, highlighting early endosomes as a central platform linking endolysosomal disruption to nuclear responses and offering potential targets for therapeutic intervention in PD.

  PublisherDOI

• Harnessing the Neurobiology of Empathy and Compassion to Alleviate Burnout in Neurology

  Annals of Neurology · 2025-11-26

  reviewOpen accessSenior authorCorresponding

  Neurologists regularly care for patients with complex, chronic, and often incurable conditions. These circumstances impose profound emotional burdens on the patient and physician. Whereas empathy is central to therapeutic effectiveness in clinical practice, sustained empathic engagement can contribute to emotional exhaustion and physician burnout, a condition now endemic in neurology. This review synthesizes insights from neuroscience, psychology, and clinical education to propose "skillful empathy" as a trainable capacity that integrates affective resonance with cognitive perspective-taking. We describe how emotional contagion harms clinician well-being and advocate for the integration of empathy training into medical education to support sustainable, compassionate neurological care. ANN NEUROL 2026;99:35-48.

  PublisherOA PDFDOI

• RAB5 Hyperactivation Induces APP‐Driven Endolysosomal and Autophagic Dysfunction in Down Syndrome: Reversal by Antisense Oligonucleotides Targeting <i>App</i> and <i>Rab5</i>

  Alzheimer s & Dementia · 2025-12-01

  articleOpen accessSenior author

  BACKGROUND: Down syndrome (DS) significantly increases the risk of Alzheimer's disease (DS-AD), with dysfunctions in the endolysosomal network (ELN) and autophagy pathways playing central roles in its pathogenesis. Dysregulation of the ELN, particularly involving RAB5 and lysosomal cathepsins, has been implicated in DS-AD, but the specific role of RAB5 hyperactivation remains poorly understood. METHODS: Postmortem brain samples from individuals with DS, DS-AD, a partial trisomy 21 case, and the Dp16 DS mouse model were examined to assess the impact of APP gene dosage on ELN and autophagy. We measured RAB5 activation, the activity of RAB7 and RAB11, their guanine nucleotide exchange factors (GEFs), lysosomal cathepsins, and autophagy-related pathways. Additionally, Dp16 mice were treated with App- and Rab5-specific antisense oligonucleotides (ASOs) to evaluate their therapeutic potential. RESULTS: Our findings revealed substantial ELN dysfunction in both DS and Dp16 brains, characterized by RAB5 hyperactivation, increased RAB7 and RAB11 activation, elevated levels of their GEFs, and increased lysosomal cathepsin levels-all in an APP dose-dependent manner. Reduced expression of TSC1/2 and hyperphosphorylation of mTOR were associated with impaired autophagy. These abnormalities were absent in a partial trisomy 21 individual with two copies of APP. Treatment with ASOs in Dp16 mice restored RAB5 activity, normalized ELN function, and improved autophagic flux, alleviating DS-AD-related pathologies including tau hyperphosphorylation, neurotrophin signaling deficits, and synaptic protein loss. CONCLUSION: Our results demonstrate that APP dose-driven RAB5 hyperactivation disrupts endosomal Rab cascades, endosome maturation, and autophagy function in DS. Targeting either APP or Rab5 may offer promising therapeutic strategies to restore cellular function and mitigate DS-AD pathologies.

  PublisherOA PDFDOI

• Antisense oligonucleotides directed against <i>App</i> and <i>Rab5</i> normalized endosomal Rab activity and reversed DS‐AD‐linked degenerative phenotypes in the Dp16 mouse model of Down syndrome

  Alzheimer s & Dementia · 2025-05-01 · 7 citations

  articleOpen accessSenior authorCorresponding

  INTRODUCTION: Down syndrome (DS) markedly raises the risk of Alzheimer's disease (DS-AD). Our findings identified widespread dysregulation of the endolysosomal network (ELN) in DS and DS-AD brains, driven by increased APP gene dose, hyperactivation of RAB5, and elevated levels of guanine nucleotide exchange factors (GEFs) for RABs 7 and 11. METHODS: We investigated whether increasing APP gene dose and RAB5 hyperactivation contributed to neuropathogenesis and whether a clinically feasible intervention could reverse ELN changes. The Dp16 DS-AD mouse model was treated with a mouse App-specific antisense oligonucleotide (App-ASO) and Rab5-specific ASOs targeting Rab5a and Rab5b. RESULTS: App-ASO treatment normalized full-length APP (fl-APP) and its products, RAB5 activity, and downstream RABs 7 and 11 pathways. Rab5-ASOs reduced RAB5 levels and restored endosomal Rab activity. Both ASO treatments mitigated DS-AD-linked pathologies. DISCUSSION: These findings highlight ELN dysregulation in DS and the therapeutic potential of ASO-based strategies targeting APP or Rab5 to counteract DS-AD features. HIGHLIGHTS: App-ASO treatment reduced the levels of APP and its products and normalized endosomal Rab activity and GEF levels in Dp16 mice. Administration of Rab5-ASOs reduced RAB5 levels and normalized endosomal Rab activity and GEF levels in Dp16 mice. Both ASO treatments were well tolerated and mitigated APP-linked pathologies including tau hyperphosphorylation, neurotrophin signaling deficits, and synaptic protein loss. App-ASO or Rab5-ASOs reversed established pathological phenotypes in Dp16 mice.

  PublisherOA PDFDOI

• Imagine, Discover, Inspire: Proceedings of the 4th International Conference of the Trisomy 21 Research Society

  NeuroMolecular Medicine · 2025-01-05 · 1 citations

  articleOpen access

  Down syndrome (DS) or trisomy 21 (T21) is present in a significant number of children and adults around the world and is associated with cognitive and medical challenges. Through research, the T21 Research Society (T21RS), established in 2014, unites a worldwide community dedicated to understanding the impact of T21 on biological systems and improving the quality of life of people with DS across the lifespan. T21RS hosts an international conference every two years to support collaboration, dissemination, and information sharing for this goal. In 2022, T21RS hosted an international conference in Long Beach, California, from June 9 to 12. The conference, attended by 483 people including scientists, families, self-advocates, and industry representatives from 17 countries, was a dynamic and interactive meeting that shared discoveries from international research teams. This summary highlights the scientific discoveries shared at the 4th T21RS meeting with the Imagine, Discover, Inspire theme.

  PublisherOA PDFDOI

• The history of Down syndrome–associated Alzheimer's disease; past, present, and future

  Alzheimer s & Dementia · 2025-06-01 · 10 citations

  articleOpen access

  The landscape of Down syndrome-associated Alzheimer's disease (DSAD) research reflects decades of scientific endeavor and collaborative effort, charting a remarkable journey from initial observations to the elucidation of complex genetic and molecular mechanisms. This perspective article chronicles key milestones and breakthroughs, paying homage to the pioneering scientists and advancements that have shaped the field. A thorough review of historical and contemporary literature offers a comprehensive narrative, highlighting the evolution of knowledge surrounding DSAD, from early recognition to the characterization of clinical presentation and natural history. The unique challenges and ethical considerations associated with DSAD populations are also examined, underscoring the importance of tailoring research and clinical approaches. By reflecting on the field's trajectory, this work celebrates past achievements while emphasizing the critical need for sustained research efforts. As part of a special issue, this article provides a foundation for appreciating the challenges and opportunities that lie ahead in advancing DSAD understanding and care. HIGHLIGHTS: This article provides a comprehensive overview of Down syndrome-associated Alzheimer's disease (DSAD) history, from early descriptions to its recognition as a genetic form of AD. It reflects on historical challenges faced by individuals with intellectual disabilities in achieving inclusion in scientific research. This historical perspective highlights the critical contributions of individuals with DS in advancing understanding of AD natural history. It explores pivotal milestones and efforts that have driven progress in DSAD research. Finally, it provides context to understand challenges and opportunities in DSAD research and its future directions.

  PublisherOA PDFDOI

• Tau pathology differs by sex in Alzheimer's disease in Down syndrome

  Alzheimer s & Dementia · 2025-10-01 · 3 citations

  articleOpen accessSenior authorCorresponding

  INTRODUCTION: Alzheimer's disease (AD), the leading cause of dementia, is more common in females. Although sex differences in tau pathology have been reported in AD, findings remain inconsistent. Down syndrome (DS), caused by trisomy 21, is the most common genetic cause of AD (DS-AD) and features tau pathology, but sex effects in DS-AD remain unclear. METHODS: We examined post mortem brain samples from individuals with DS-AD, DS without AD, and a rare partial trisomy 21 (PT) case with only two amyloid precursor protein (APP) gene copies. PHF1 tau, total tau, and sarkosyl-soluble and insoluble fractions were quantified by group and sex. RESULTS: PHF1 tau was significantly elevated in DS-AD, especially in females. Lower total tau in DS-AD males explained the absence of sex differences after normalization. Sarkosyl-insoluble tau was also higher in DS-AD females. DS without AD, and the PT case showed minimal pathology. DISCUSSION: These findings suggest sex-specific tau dynamics in DS-AD and support a role for APP dosage. HIGHLIGHTS: Tau pathology is significantly elevated in individuals with DS-AD, especially in females. Female DS-AD brains show markedly higher PHF1 (S396/404) and sarkosyl-insoluble tau levels compared to males. The observed sex difference in phosphorylated tau is driven by lower total tau in DS-AD males. Minimal tau pathology is present in DS without AD and in a rare partial trisomy 21 case. These findings implicate APP gene dosage in tau pathology in DS-AD.

  PublisherOA PDFDOI

• Hyperactivation of RAB5 disrupts the endosomal Rab cascade leading to endolysosomal dysregulation in Down syndrome: A necessary role for increased <i>APP</i> gene dose

  Alzheimer s & Dementia · 2025-05-01 · 8 citations

  articleOpen accessSenior authorCorresponding

  INTRODUCTION: Down syndrome (DS) markedly increases the risk of Alzheimer's disease (DS-AD), but the role of RAB5 hyperactivation in its pathogenesis remains unclear. METHODS: Postmortem brain samples from individuals with DS, with and without AD, and a partial trisomy 21 case with only two amyloid precursor protein (APP) gene copies, were examined for endosomal Rabs, their guanine-nucleotide exchange factor (GEF) and GTPase activating protein (GAP) levels, and lysosomal cathepsins. Analysis extended to the Dp16 DS mouse model. The role of RAB5 hyperactivation in disrupting the endolysosomal system was explored using primary neurons. RESULTS: We observed widespread endolysosomal dysregulation in DS and Dp16 brains, requiring increased APP gene dose. RAB5 hyperactivation resulted in increased activation of endosomal Rabs, including RABs 7 and 11, and increased recruitment of Rabs and their GEFs to early endosomes as well as the levels of lysosomal cathepsins. DISCUSSION: These findings suggest that APP dose-driven RAB5 hyperactivation disrupts endosomal Rab cascades and endosome maturation in DS. HIGHLIGHTS: There is widespread disruption of the endolysosomal network in the Down syndrome (DS) brain and in the Dp16 mouse model brain. Amyloid precursor protein (APP) gene dose was necessary for increases in endosomal Rab activity and lysosomal cathepsins in both human and mouse brains. Changes in endosomal Rabs 7 and 11 were linked to increases in their guanine-nucleotide exchange factors (GEFs) and GEF/GTPase activating protein (GAP) ratios. Mechanistic studies demonstrated essential roles for the beta-C-terminal fragment (β-CTF) of APP acting through hyperactivation of RAB5 to increase early endosomal membrane binding of the GEFs for downstream endosomal Rabs. RAB5 acts as the central hub for disruptions in endolysosomal function in DS.

  PublisherDOI

• Down Syndrome: Progress in Defining Pathogenesis and Treatments for Neurodevelopmental Deficits and Alzheimer’s Disease

  Translational Neuroscience · 2025-01-01

  book-chapterOpen accessSenior author

  Down syndrome (DS) is a high-incidence (1:750–1000) genetic condition [93] caused by an extra copy of chromosome 21 (Chr21; HSA21) [211]. Among the various DS-linked traits, such as cardiac abnormalities and gastrointestinal disorders [49], intellectual disability (ID), which is defined by an intelligence quotient <70, is a fully penetrant phenotype [23, 223, 409] and a source of major concern to parents and relatives. In children with DS, IQ score is usually in the moderately to severely retarded range (IQ = 25–55) and decreases progressively with age [371]. Children and adults with DS exhibit deficits in a constellation of brain functions, such as memory, executive functions, language, and verbal and motor skills [62, 86, 133, 370, 371]. Understanding the nature of cognitive deficits in DS is important for understanding their biological bases, timing, and approaches to treatment. While using standardized tests, there is evidence of progressive decline, and a different pattern emerges when raw scores are examined longitudinally [133]. For example, Couzens et al. (2011), assessing raw scores for different cognitive functions, show clear increases with increasing age. Though the measures in all tests in 4-year-old children with DS were lower than in cognitively normal subjects, tests of vocabulary, comprehension, and quantitative function (so-called crystallized abilities) showed increases in performance from ages 4 through ~20 years, with apparent stabilization, or relatively modest decrements, through age 25. Interestingly, raw scores of vocabulary were stable through age ~30. In contrast, raw scores for pattern analysis (a measure of fluid ability) showed progressive improvements that continued beyond age 20. The findings show that cognitive deficits in DS are not fixed but pursue a different developmental trajectory with lesser gains relative to cognitive normals. Marked decrements linked to dementia ensue only later. Indeed, after age 40, adults with DS are at a high risk of developing Alzheimer’s disease (AD) [410]. During the past 20 years, research has made great strides in defining how trisomy of HSA21 affects cognition in early and later life. Yet, despite increasing knowledge, there are no treatments for ID or AD in DS. Herein, we discuss the efforts made to address this topic and neurobiological discoveries and insights that may lead to effective treatments.

  PublisherDOI

Recent grants

• NIH Grant P01NS092525

  NIH · $12.5M · 2022

• NIH Grant R01AG010672

  NIH · $884k · 1997

• NIH Grant R01NS024054

  NIH · $3.9M · 2009

• NIH Grant R01AG016999

  NIH · $2.8M · 2005

• Antisense Oligonucleotides targeting APP to prevent neurodegeneration in models of Down Syndrome and Alzheimer's disease

  NIH · $2.9M · 2019–2025

Frequent coauthors

• Pavel V. Belichenko

  University of California, San Diego

  68 shared

• Chengbiao Wu

  45 shared

• Ahmad Salehi

  42 shared

• Alexander M. Kleschevnikov

  University of California, San Diego

  41 shared

• Yichao Yu

  General Administration of Sport of China

  34 shared

• Alfred C. Server

  University of California Hastings College of the Law

  31 shared

• J Valletta

  University of California, San Diego

  30 shared

• Eric M. Shooter

  29 shared

Labs

• Department of Cellular and Systems PharmacologyPI

Education

• Ph.D.

  University of Florida College of Pharmacy

• M.S.

  Idaho State University College of Pharmacy

• B.S.

  Nova Southeastern University College of Pharmacy

Awards & honors

• Jean Lamberti Mentorship Award (2022)
• Florida Pharmacy Association Pharmaceutics Innovation and Te…
• American Association of Colleges of Pharmacy Teacher of the…