Diane E. Wakeham, Ph.D.

All Publications

• Peripheral complement C4 protein in schizophrenia: Association with gene copy number and immune cell subtypes. Proceedings of the National Academy of Sciences of the United States of America Kalinowski, A., Macaubas, C., Guo, H., Anker, L. A., Wakeham, D. E., Ho, M., Pattni, R., Bayram, B., Sharma, S., Liliental, J., Yoon, J. H., Mellins, E. D., Steinman, L., Urban, A. E. 2026; 123 (20): e2536376123

  Abstract

  The lack of highly effective disease-modifying treatments for schizophrenia necessitates exploration of novel aspects of its pathophysiology, including attention to innate immune mechanisms outside the brain. C4 protein activation, associated with the complement cascade of innate immunity, associates with symptoms and predicts outcomes in schizophrenia. However, C4 protein activation does not coincide with expected changes to other proteins in the complement cascade, suggesting another source of C4 protein activation. Studying a combination of fresh whole blood from 10 anonymous donors and a large set of publicly available microarray data, we show that C4 protein is found and expressed primarily in neutrophils and monocytes. Then, we compared the correlation between C4 protein in neutrophils, classical monocytes, plasma, and the number of C4A gene copies. We determined the number of C4A genes using digital droplet PCR, C4 protein in neutrophils (15 patients/21 controls) and plasma (30 patients/38 controls) using Western blotting, and classical monocytes (30 patients/38 controls) using flow cytometry. We found a large positive correlation between the number of C4A gene copies and the amount of C4 protein only in neutrophils and only in the schizophrenia group (Spearman's rho = 0.63, 95% BCa CI: 0.12 to 0.89, P = 0.012). Our results indicate a convergence of innate immunity mechanisms associated with schizophrenia. The involvement of innate immunity deserves further attention to determine whether it could be a target for therapy in schizophrenia.

  View details for DOI 10.1073/pnas.2536376123

  View details for PubMedID 42113976

• A Qualitative Study of Family Experiences of the Peer Supported Family Intervention, Psychosis Recovery by Enabling Adult Carers at Home (Psychosis REACH), in an Early Psychosis Clinic. Early intervention in psychiatry Lean, M., Benitah, K. C., Wakeham, D. E., Virtheim, D., Kopelovich, S. L., Hardy, K. 2026; 20 (7): e70210

  Abstract

  Family members play an important role in supporting their loved ones with first episode psychosis (FEP), but few have access to interventions demonstrated to support them in this endeavour. Psychosis REACH (Recovery by Enabling Adult Carers at Home; p-REACH) is a family intervention for psychosis (FIp), delivered directly to families by clinicians and peers, that provides both psychoeducation and Cognitive Behavioural Therapy for psychosis (CBT-p) informed skills to family carers. This study aimed to qualitatively explore family participants' experiences of receiving the p-REACH intervention and assess its feasibility and acceptability within an early psychosis service.Following the p-REACH intervention, all participants were invited to partake in qualitative interviews and analysed using a Reflexive Thematic Analysis approach.Family carers reported positive experiences with the intervention. Key themes indicated that it helped build (1) internal resources, as participants valued increasing their knowledge and understanding of psychosis and learning skills to support themselves and their loved ones-leading to greater confidence and (2) external resources, as the group-based, peer-supported format enhanced their sense of connection with their loved ones and with other families.This study demonstrates that the intervention was both feasible and acceptable to participants in an early psychosis setting. It contributes to the growing body of evidence supporting the positive impact of family interventions in psychosis, specifically the teaching of CBTp skills to caregivers of those with early psychosis.

  View details for DOI 10.1111/eip.70210

  View details for PubMedID 42397114

• A Pilot Study of the Peer Supported Family Intervention, Psychosis Recovery by Enabling Adult Carers at Home (Psychosis-REACH) in an Early Psychosis Clinic. Early intervention in psychiatry Lean, M., Benitah, K. C., Wakeham, D. E., Chang, L., Virtheim, D., Runestad, S., Kopelovich, S. L., Hardy, K. V. 2026; 20 (4): e70169

  Abstract

  Psychosis REACH (p-REACH) is a co-produced, bichronous (hybrid synchronous and asynchronous) Family Intervention for psychosis that leverages a direct-to-family delivery model to enhance access. We aimed to assess the effect, feasibility and acceptability of the p-REACH core training when combined with longitudinal, family peer-delivered support in an early psychosis setting.After completing the p-REACH core training, caregiver participants (N = 20) engaged in monthly peer and clinician co-led coaching groups for 6 months to support skill development and met with a peer with lived experience of caring for a loved one with psychosis twice a month for the course of the intervention. We assessed depression, anxiety, expressed emotion, perceptions of carer burden and attitudes towards psychosis at baseline, immediately post-intervention and at 3 and 6 months post-intervention, the latter of which coincided with the end of the coaching period.The intervention, combined with ongoing peer facilitated group and individual family support, had a positive impact on all carers' outcomes, except depression which was subthreshold at baseline.This study demonstrates the feasibility and acceptability of the p-REACH intervention in an early psychosis clinic and demonstrates the positive impact of teaching CBTp-informed skills to caregivers on both carer and service user outcomes. Further randomised controlled studies are needed to fully assess the key components and impact of this intervention.

  View details for DOI 10.1111/eip.70169

  View details for PubMedID 41902572

• Ketogenic Diet Intervention on Metabolic and Psychiatric Health in Bipolar and Schizophrenia: A Pilot Trial. Psychiatry research Sethi, S., Wakeham, D., Ketter, T., Hooshmand, F., Bjornstad, J., Richards, B., Westman, E., Krauss, R. M., Saslow, L. 2024; 335: 115866

  Abstract

  The ketogenic diet (KD, also known as metabolic therapy) has been successful in the treatment of obesity, type 2 diabetes, and epilepsy. More recently, this treatment has shown promise in the treatment of psychiatric illness. We conducted a 4-month pilot study to investigate the effects of a KD on individuals with schizophrenia or bipolar disorder with existing metabolic abnormalities. Twenty-three participants were enrolled in a single-arm trial. Results showcased improvements in metabolic health, with no participants meeting metabolic syndrome criteria by study conclusion. Adherent individuals experienced significant reduction in weight (12 %), BMI (12 %), waist circumference (13 %), and visceral adipose tissue (36 %). Observed biomarker enhancements in this population include a 27 % decrease in HOMA-IR, and a 25 % drop in triglyceride levels. In psychiatric measurements, participants with schizophrenia showed a 32 % reduction in Brief Psychiatric Rating Scale scores. Overall Clinical Global Impression (CGI) severity improved by an average of 31 %, and the proportion of participants that started with elevated symptomatology improved at least 1-point on CGI (79 %). Psychiatric outcomes across the cohort encompassed increased life satisfaction (17 %) and enhanced sleep quality (19 %). This pilot trial underscores the potential advantages of adjunctive ketogenic dietary treatment in individuals grappling with serious mental illness.

  View details for DOI 10.1016/j.psychres.2024.115866

  View details for PubMedID 38547601

• Evolutionary analysis and molecular dissection of caveola biogenesis JOURNAL OF CELL SCIENCE Kirkham, M., Nixon, S. J., Howes, M. T., Abi-Rached, L., Wakeham, D. E., Hanzal-Bayer, M., Ferguson, C., Hill, M. M., Fernandez-Rojo, M., Brown, D. A., Hancock, J. F., Brodsky, F. M., Parton, R. G. 2008; 121 (12): 2075-2086

  Abstract

  Caveolae are an abundant feature of mammalian cells. Integral membrane proteins called caveolins drive the formation of caveolae but the precise mechanisms underlying caveola formation, and the origin of caveolae and caveolins during evolution, are unknown. Systematic evolutionary analysis shows conservation of genes encoding caveolins in metazoans. We provide evidence for extensive and ancient, local and genomic gene duplication, and classify distinct caveolin gene families. Vertebrate caveolin-1 and caveolin-3 isoforms, as well as an invertebrate (Apis mellifera, honeybee) caveolin, all form morphologically identical caveolae in caveolin-1-null mouse cells, demonstrating that caveola formation is a conserved feature of evolutionarily distant caveolins. However, coexpression of flotillin-1 and flotillin-2 did not cause caveola biogenesis in this system. In contrast to the other tested caveolins, C. elegans caveolin is efficiently transported to the plasma membrane but does not generate caveolae, providing evidence of diversity of function in the caveolin gene family. Using C. elegans caveolin as a template to generate hybrid caveolin constructs we now define domains of caveolin required for caveolae biogenesis. These studies lead to a model for caveola formation and novel insights into the evolution of caveolin function.

  View details for DOI 10.1242/jcs.024588

  View details for Web of Science ID 000256470100015

  View details for PubMedID 18505796

• Clathrin heavy and light chain isoforms originated by independent mechanisms of gene duplication during chordate evolution PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wakeham, D. E., Abi-Rached, L., Towler, M. C., Wilbur, J. D., Parham, P., Brodsky, F. M. 2005; 102 (20): 7209-7214

  Abstract

  In humans, there are two isoforms each of clathrin heavy chain (CHC17 and CHC22) and light chain (LCa and LCb) subunits, all encoded by separate genes. CHC17 forms the ubiquitous clathrin-coated vesicles that mediate membrane traffic. CHC22 is implicated in specialized membrane organization in skeletal muscle. CHC17 is bound and regulated by LCa and LCb, whereas CHC22 does not functionally interact with either light chain. The imbalanced interactions between clathrin subunit isoforms suggest a distinct evolutionary history for each isoform pair. Phylogenetic and sequence analysis placed both heavy and light chain gene duplications during chordate evolution, 510-600 million years ago. Genes encoding CHC22 orthologues were found in several vertebrate species, with only a pseudogene present in mice. Multiple paralogons surrounding the CHC genes (CLTC and CLTD) were identified, evidence that genomic or large-scale gene duplication produced the two CHC isoforms. In contrast, clathrin light chain genes (CLTA and CLTB) apparently arose by localized duplication, within 1-11 million years of CHC gene duplication. Analysis of sequence divergence patterns suggested that structural features of the CHCs were maintained after gene duplication, but new interactions with regulatory proteins evolved for the CHC22 isoform. Thus, independent mechanisms of gene duplication expanded clathrin functions, concomitant with development of neuromuscular sophistication in chordates.

  View details for DOI 10.1073/pnas.0502058102

  View details for Web of Science ID 000229292200029

  View details for PubMedID 15883369

  View details for PubMedCentralID PMC1091751

• Clathrin self-assembly involves coordinated weak interactions favorable for cellular regulation. The EMBO journal Wakeham, D. E., Chen, C. Y., Greene, B., Hwang, P. K., Brodsky, F. M. 2003; 22 (19): 4980-90

  Abstract

  The clathrin triskelion self-assembles into a polyhedral coat surrounding membrane vesicles that sort receptor cargo to the endocytic pathway. A triskelion comprises three clathrin heavy chains joined at their C-termini, extending into proximal and distal leg segments ending in a globular N-terminal domain. In the clathrin coat, leg segments entwine into parallel and anti-parallel interactions. Here we define the contributions of segmental interactions to the clathrin assembly reaction and measure the strength of their interactions. Proximal and distal leg segments were found to lack sufficient affinity to form stable homo- or heterodimers under assembly conditions. However, chimeric constructs of proximal or distal leg segments, trimerized by replacement of the clathrin trimerization domain with that of the invariant chain protein, were able to self-assemble in reversible reactions. Thus clathrin assembly occurs because weak leg segment affinities are coordinated through trimerization, sharing a dependence on multiple weak interactions with other biopolymers. Such polymerization is sensitive to small environmental changes and is therefore compatible with cellular regulation of assembly, disassembly and curvature during formation of clathrin-coated vesicles.

  View details for DOI 10.1093/emboj/cdg511

  View details for PubMedID 14517237

  View details for PubMedCentralID PMC204494

• Biological basket weaving: formation and function of clathrin-coated vesicles. Annual review of cell and developmental biology Brodsky, F. M., Chen, C. Y., Knuehl, C., Towler, M. C., Wakeham, D. E. 2001; 17: 517-68

  Abstract

  There has recently been considerable progress in understanding the regulation of clathrin-coated vesicle (CCV) formation and function. These advances are due to the determination of the structure of a number of CCV coat components at molecular resolution and the identification of novel regulatory proteins that control CCV formation in the cell. In addition, pathways of (a) phosphorylation, (b) receptor signaling, and (c) lipid modification that influence CCV formation, as well as the interaction between the cytoskeleton and CCV transport pathways are becoming better defined. It is evident that although clathrin coat assembly drives CCV formation, this fundamental reaction is modified by different regulatory proteins, depending on where CCVs are forming in the cell. This regulatory difference likely reflects the distinct biological roles of CCVs at the plasma membrane and trans-Golgi network, as well as the distinct properties of these membranes themselves. Tissue-specific functions of CCVs require even more-specialized regulation and defects in these pathways can now be correlated with human diseases.

  View details for DOI 10.1146/annurev.cellbio.17.1.517

  View details for PubMedID 11687498

• Molecular structures of proteins involved in vesicle fusion. Traffic (Copenhagen, Denmark) Ybe, J. A., Wakeham, D. E., Brodsky, F. M., Hwang, P. K. 2000; 1 (6): 474-9

  Abstract

  We present a summary of the structures of 13 proteins involved in the docking and fusion of intracellular transport vesicles to their target membranes.

  View details for DOI 10.1034/j.1600-0854.2000.010605.x

  View details for PubMedID 11208133

• Molecular structures of proteins involved in vesicle coat formation. Traffic (Copenhagen, Denmark) Wakeham, D. E., Ybe, J. A., Brodsky, F. M., Hwang, P. K. 2000; 1 (5): 393-8

  Abstract

  This review includes 16 structures of vesicle coat components and accessory proteins and a description of their roles in vesicle budding or coat disassembly.

  View details for DOI 10.1034/j.1600-0854.2000.010504.x

  View details for PubMedID 11208125

• Pesticide exposures to children from California's Central Valley: results of a pilot study. Journal of exposure analysis and environmental epidemiology Bradman, M. A., Harnly, M. E., Draper, W., Seidel, S., Teran, S., Wakeham, D., Neutra, R. 1997; 7 (2): 217-34

  Abstract

  In response to concerns about pesticide use and evidence that contaminants may accumulate in house dust, the California Department of Health Services (DHS) conducted a pilot study of pesticide contamination in rural children's home environments. House dust samples for pesticide analysis were collected from eleven homes, five of which had at least one farmworker (FW) resident. Handwipe samples were collected from one child at each residence (ages 1-3 years). Ten of 33 pesticides tested in house dust were detected. Excluding non-detects, concentrations for diazinon ranged from 0.7-169 ppm in four FW homes and 0.2-2.5 ppm in three non-farmworker (NFW) homes (overall median = 1 ppm), suggesting a difference between FW and NFW homes. Chlorpyrifos ranged from 0.2-33 ppm in three FW homes and < 1 ppm in two NFW homes (overall median < 0.5 ppm). All other pesticides were detected at < 2 ppm at four or fewer homes. The sources of these compounds could not be determined. Co-located samples were considerably different in concentration and loading, indicating intra-household variation. Of nine compounds tested, diazinon and chlorpyrifos were found on the hands of two or three FW children (20-220 ng/hand). Dust ingestion scenarios show child exposures could exceed the United States Environmental Protection Agency Office of Pesticide Program diazinon chronic reference dose (9 x 10(5) mg/kg/day). The results suggested that pesticide residues are present in the home environment of some California children and are likely to contribute to exposures. Additional research is feasible and needed to assess the magnitude and distribution of these risks.

  View details for PubMedID 9185013

• RATE CONSTANTS FOR METAM-SODIUM CLEAVAGE AND PHOTODECOMPOSITION IN WATER JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY DRAPER, W. M., WAKEHAM, D. E. 1993; 41 (7): 1129-1133

  View details for DOI 10.1021/jf00031a023

  View details for Web of Science ID A1993LP13500023