About

Lawrence Goldstein is an Emeritus Professor of Cellular and Molecular Medicine at UCSD. His research focuses on unraveling how molecular motors interact with and control the behavior of axonal vesicles, and relating this understanding to the molecular basis of neuronal defects in Alzheimer's Disease (AD) and Niemann Pick type C disease. His work utilizes pluripotent stem cell lines containing known mutations that cause hereditary Alzheimer's disease and Niemann Pick Type C disease, with the aim of understanding cholesterol trafficking and transport in relation to dementia. Goldstein's lab also probes basic mechanisms of vesicle movement and sorting in neurons, and how genetic variation predisposes individuals to different neuronal phenotypes and diseases, including sporadic Alzheimer's disease. He has developed quantitative methods for generating and evaluating neurons from human embryonic stem cells and induced pluripotent stem cells, and collaborates on developing potential therapies for ALS using human embryonic stem cells to generate astrocyte progenitors. His research areas include genetics and genomics, membrane trafficking, neurodevelopment, and neurodegenerative disease.

Research topics

• Biology
• Cell biology
• Genetics
• Neuroscience
• Internal medicine
• Biochemistry

Selected publications

• Challenges and Opportunities for Consideration of Efavirenz Drug Repurposing for Alzheimer’s Disease Therapeutics

  ACS Pharmacology & Translational Science · 2024-09-06 · 5 citations

  reviewOpen access

  Therapeutic research and development for Alzheimer's disease (AD) has been an area of intense research to alleviate memory loss and neurodegeneration. There is growing interest in drug repositioning and repurposing strategies for FDA-approved medications as potential candidates that may further advance AD therapeutics. The FDA drug efavirenz has been investigated as a candidate drug for repurposing as an AD medication. The proposed mechanism of action of efavirenz (at low doses) is the activation of the neuron-specific enzyme CYP46A1 that converts excess brain cholesterol into 24-hydroxycholesterol (24-HC) that is exported to the periphery. Efavirenz at a low dose was found to improve memory deficit in the 5XFAD model of AD that was accompanied by elevated 24-HC and reduction in Aβ; furthermore, efavirenz reduced pTau and excess cholesterol levels in human iPSC-derived Alzheimer's neurons. The low dose of efavirenz used in the AD mouse model to increase 24-HC contrasts with the use of more than 100-fold higher doses of efavirenz for clinical treatment of human immunodeficiency virus (HIV) through inhibition of reverse transcriptase. Low doses of efavirenz may avoid neurotoxic adverse effects that occur at high efavirenz doses used for HIV treatment. This review evaluates the drug properties of efavirenz with respect to its preclinical data on regulating memory deficit, pharmacokinetics, pharmacodynamics, metabolites, and genetic variabilities in drug metabolism as well as its potential adverse effects. These analyses discuss the challenges and questions that should be addressed in future studies to consider the opportunity for low dose efavirenz as a candidate for AD drug development.

  PublisherDOI

• Unraveling Alpha-Gal Syndrome: A Case Study of a Rare Meat Allergy

  Cureus · 2024-07-26 · 2 citations

  articleOpen accessSenior author

  Allergies are a very common pathology and their manifestations consist of a spectrum of presentations, ranging from minimal discomfort like a runny nose to lethal reactions like anaphylaxis and death. Meat allergy is not a very common form of allergy, even though there is a relatively high level of meat consumption. One of the rare forms of non-primate mammalian meat allergy is alpha-gal syndrome (AGS). It is related to IgE antibodies specific for galactose-α-1,3-galactose (α-Gal). It is triggered in sensitized individuals due to multiple bites of lone star tick bites (Amblyomma americanum). Here we present a 63-year-old male with a complaint of recurrent hives and tongue swelling, developed recently after traveling to Twinsburg, OH. There is no significant history of any allergic conditions. Vital signs were stable with a normal physical examination. The patient had normal routine labs including eosinophil count, thyroid-stimulating hormone (TSH), iron panel, and negative HIV. Allergy testing showed normal total IgE but increased levels of IgE for allergens like beef, lamb, and pork (18.4, 6.71, and 7.62 respectively) and greatly increased levels of IgE for alpha-gal (42.7). Sensitization to alpha-gal can cause delayed allergic symptoms upon consuming various non-primate mammalian types of meat, particularly beef, pork, and lamb. Conditions like AGS are rare and can be missed as an initial diagnosis in many patients. A high degree of vigilance is required to diagnose such conditions.

  PublisherOA PDFDOI

• HPR142 Review of Gene Therapy Access Landscape

  Value in Health · 2024-06-01

  article
  PublisherDOI

• Human iPSC‐derived neuron modeling for the study of early‐onset Alzheimer’s disease

  Alzheimer s & Dementia · 2024-12-01

  articleOpen access

  Abstract Background Early‐onset Alzheimer’s disease (EOAD) is a complex disease that occurs at an early age at onset (AAO) before 65 years, constituting 5‐6% of all AD cases and remains poorly understood. Patient‐derived induced pluripotent stem cells (iPSCs) have been used to model different forms of EOAD that display heterogeneous disease mechanisms. Method We examined iPSC‐derived neurons from both familial EOAD harboring mutations in PSEN1 A79V , PSEN2 N141I , and APP V717I and non‐familial EOAD patients at an early AAO. RNA‐seq for familial and non‐familial EOAD patients as well as ATAC‐seq for familial EOAD patients were carried out to characterize the gene expression and chromatin accessibility changes, respectively. Differential expression and enrichment analysis, TF activity identification, and co‐expression module detection were performed for familial EOAD RNA‐seq. Clustering and surrogate neuron marker classification were performed for non‐familial EOAD RNA‐seq. Differential peak analysis, TF motif footprinting and peak functional enrichment were performed for familial EOAD ATAC‐seq. Result Our approach allowed us to identify the correlation between gene expression and chromatin accessibility associated with key disease familial EOAD endotypes. We identified limitations with our non‐familial EOAD neuron model to study sporadic AD, providing evidence that these neurons present variation of differentiation across patient clones, patient variability and an immature culture state. Common endotypes were identified across three familial EOAD mutations such as dedifferentiation of a mature neuron to a less differentiated quasi‐neuron state and repression of mitochondrial function and metabolism. Integrative analysis allowed us to ascertain the master transcriptional regulators associated with these endotypes, including REST, ASCL1, and ZIC family members (activation), as well as NRF1 (repression). Our non‐familial EOAD study showed a modest difference in expression profiling and a limited number of differentially expressed genes (DEGs) between diseased and control subjects. Conclusion iPSC‐derived neurons demonstrated that familial EOAD mutations share common regulatory changes within endotypes with varying severity, leading to reversion to a less‐differentiated neuron state. Extending the usage of these neurons to non‐familial EOAD may not serve as ideal to study sporadic AD. Overall, we have demonstrated that human neuron modeling can be applied to different forms of EOAD to understand the disease etiology better.

  PublisherOA PDFDOI

• Human fetal tissue is critical for biomedical research

  Stem Cell Reports · 2023-11-16 · 12 citations

  reviewOpen accessSenior author

  Human fetal tissue and cells derived from fetal tissue are crucial for biomedical research. Fetal tissues and cells are used to study both normal development and developmental disorders. They are broadly applied in vaccine development and production. Further, research using cells from fetal tissue is instrumental for studying many infectious diseases, including a broad range of viruses. These widespread applications underscore the value of fetal tissue research and reflect an important point: cells derived from fetal tissues have capabilities that cells from other sources do not. In many cases, increased functionality of cells derived from fetal tissues arises from increased proliferative capacity, ability to survive in culture, and developmental potential that is attenuated in adult tissues. This review highlights important, representative applications of fetal tissue for science and medicine.

  PublisherOA PDFDOI

• Asbestos Exposure and Development of Pulmonary Pleomorphic Carcinoma in a Non-smoker: A Rare Non-small Cell Lung Cancer

  Cureus · 2023-04-20

  articleOpen access

  Pulmonary pleomorphic carcinoma (PPC) is a subtype of non-small cell lung cancer that is extremely rare and carries a poor prognosis due to its inadequate response to treatment. Patients that present with PPC often exhibit similar symptoms of other malignancies of the lung, making it hard for clinicians to distinguish between each type. However, cytology and gene mutation testing are two approaches that can aid physicians in an accurate and definitive diagnosis. We present a case of an 88-year-old male patient with a diagnosis of pulmonary pleomorphic carcinoma after experiencing recurrent sanguineous pleural effusions. The patient had no smoking history but did have a history of asbestos exposure and pulmonary fibrosis. The patient underwent thoracotomy with pleurodesis and analysis of the surgical pleural biopsy specimen stained positive for markers indicative of PPC. The pathology report was also consistent with the associated cell morphology. Lung cancer is the leading cause of mortality due to cancer in the United States, and exposure to certain substances contributes to the development of these poorly treatable lung malignancies. Smoking and asbestos exposure are well known to act synergistically with each other as risk factors in developing these lung malignancies. In addition to clinical suspicion, screening for these risk factors with laboratory values and imaging is important to diagnose these rare cases of lung malignancies.

  PublisherOA PDFDOI

• Limitations of the human iPSC-derived neuron model for early-onset Alzheimer’s disease

  Molecular Brain · 2023-11-03 · 3 citations

  articleOpen access

  Non-familial Alzheimer's disease (AD) occurring before 65 years of age is commonly referred to as early-onset Alzheimer's disease (EOAD) and constitutes ~ 5-6% of all AD cases (Mendez et al. in Continuum 25:34-51, 2019). While EOAD exhibits the same clinicopathological changes such as amyloid plaques, neurofibrillary tangles (NFTs), brain atrophy, and cognitive decline (Sirkis et al. in Mol Psychiatry 27:2674-88, 2022; Caldwell et al. in Mol Brain 15:83, 2022) as observed in the more prevalent late-onset AD (LOAD), EOAD patients tend to have more severe cognitive deficits, including visuospatial, language, and executive dysfunction (Sirkis et al. in Mol Psychiatry 27:2674-88, 2022). Patient-derived induced pluripotent stem cells (iPSCs) have been used to model and study penetrative, familial AD (FAD) mutations in APP, PSEN1, and PSEN2 (Valdes et al. in Research Square 1-30, 2022; Caldwell et al. in Sci Adv 6:1-16, 2020) but have been seldom used for sporadic forms of AD that display more heterogeneous disease mechanisms. In this study, we sought to characterize iPSC-derived neurons from EOAD patients via RNA sequencing. A modest difference in expression profiles between EOAD patients and non-demented control (NDC) subjects resulted in a limited number of differentially expressed genes (DEGs). Based on this analysis, we provide evidence that iPSC-derived neuron model systems, likely due to the loss of EOAD-associated epigenetic signatures arising from iPSC reprogramming, may not be ideal models for studying sporadic AD.

  PublisherOA PDFDOI

• Human-Induced Pluripotent Stem Cell (hiPSC)-Derived Neurons and Glia for the Elucidation of Pathogenic Mechanisms in Alzheimer’s Disease

  Methods in molecular biology · 2022-11-18 · 10 citations

  reviewOpen accessSenior author
  PublisherOA PDFDOI

• Brain organoids, consciousness, ethics and moral status

  Seminars in Cell and Developmental Biology · 2022-03-23 · 59 citations

  reviewOpen access
  PublisherOA PDFDOI

• Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients

  Cell stem cell · 2021 · 244 citations

  • Biology
  • Neuroscience
  • Cell biology
  PublisherOA PDFDOI

Recent grants

• NIH Grant RC1NS068705

  NIH · $1.0M · 2012

• NIH Grant R01GM035252

  NIH · $5.1M · 2007

• NIH Grant R21AG038849

  NIH · $336k · 2013

• Training Program in Basic and Clinical Genetics

  NIH · $8.9M · 1998–2023

• REGULATORY GENOMIC STUDIES IN A COHORT OF IPS CELL DERIVED CARDIOMYOCYTES

  NIH · $9.8M · 2011–2017

Frequent coauthors

• Elizabeth A. Roberts

  University of California, San Diego

  65 shared

• Fred H. Gage

  Salk Institute for Biological Studies

  56 shared

• Austin Smith

  53 shared

• Irving L. Weissman

  Stanford University

  52 shared

• Fiona M. Watt

  European Molecular Biology Organization

  50 shared

• Rudolf Jaenisch

  Whitehead Institute for Biomedical Research

  50 shared

• J. B. Gurdon

  University of Cambridge

  50 shared

• Ernest Memorial

  Wellcome/MRC Cambridge Stem Cell Institute

  50 shared

Education

• Ph.D., Molecular Biology

  University of California, San Diego

  1981

• B.S., Biology

  University of California, San Diego

  1976