Clinical Neuroscience, Neurogenetics, and Neurological Disorders
Dr. Ward received his B.S. from Kenyon College in 1999 and M.D. and Ph.D. degrees from Washington University in St. Louis in 2007. As a graduate student, he worked in Yi Rao’s lab and studied the regulation of cell migration during neurodevelopment. Following a neurology residency at the University of California in San Francisco, he sub-specialized in behavioral neurology and completed a postdoctoral fellowship in Li Gan’s lab studying basic mechanisms of frontotemporal dementia. As a fellow he received an American Brain Foundation CRTF award and a NIH K08 career development award. In 2015 he joined the NINDS as an Assistant Clinical Investigator and later became a Senior Investigator leading the Inherited Neurodegenerative Diseases Section of the Neurogenetics Branch. His research focuses on identifying intersecting mechanisms of neurodegenerative diseases, with an ultimate goal of developing targeted, disease-modifying therapies for affected patients.
Lab Overview
The Inherited Neurodegenerative Diseases Section focuses on the biological abnormalities that underlie inherited neurodegenerative diseases, with a goal of translating new insights into effective therapies for affected patients. Using genetically-engineered iPSC derived neurons as experimental platforms, we study how disease-related gene mutations alter the function of molecular networks within cells. Our projects rely on a combination of ‘omics, molecular, biochemical, and imaging techniques.
Neurodegenerative diseases are common, debilitating, and often untreatable. We believe that a better understanding of the basic biology of these diseases will serve as a foundation upon which to develop effective therapies. Our group focuses on two related neurodegenerative diseases, frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). These diseases are often inherited, and although many of the causal genes are known we don’t understand the normal function of their encoded proteins or how mutations in these genes alters upstream biological processes.
FTD and ALS
FTD is a progressive neurodegenerative disease that causes behavioral changes and language dysfunction. ALS is a neuromuscular disease that causes progressive motor decline and paralysis. Neither disease is treatable.
FTD causes loss of neurons in the frontal and temporal lobes of the cerebral cortex, while ALS causes death of motor neurons in the brain and spinal cord. Curiously, these apparently divergent diseases are related at the clinical, pathological, and genetic level. Patients with FTD frequently develop additional motor neuron degeneration, and patients with ALS often have co-existent FTD. Pathologically, FTD and ALS are often characterized by accumulations of the same aggregated proteins. Genetically, FTD and ALS can be caused by inherited mutations in the same genes. Despite remarkable progress in identifying many of the genes associated with FTD and ALS, we know relatively little about how mutations in these genes cause disease.
Identification of converging mechanisms of FTD/ALS
Heroic efforts over the past few decades by human geneticists have identified most of the genes associated with familial forms of FTD/ALS. In parallel, technical revolutions in stem cell biology, genome engineering, and ‘omics now allow us to interrogate the function of these genes in disease-relevant cellular models. In the context of these advances, our field is poised to make giant leaps in understanding the molecular underpinnings of these related diseases.
Of the roughly 40 genes associated with FTD/ALS, the majority encode proteins that appear to regulate endolysosomal biology or are components of ribonuclear protein (RNP) complexes. It is likely that at least some of these proteins regulate converging biological pathways, given the similar clinical and pathological phenotypes that ensue when mutations alter their function. For example, individuals with homozygous mutations in the GRN gene, which cause complete loss of progranulin expression, cause a lysosomal storage disease known as neuronal ceroid lipofuscinosis (NCL). We recently found that individuals with FTD-related heterozygous mutations in the GRN gene develop accumulations of pathologic Aggregates of TDP-43 in the brain of an FTD patientlysosomal storage material. Progranulin localizes to the lysosome, suggesting a crucial (but undefined) role in regulation of lysosomal biology. Numerous additional FTD/ALS-related genes also regulate endolysosomal biology, including TMEM106B, which encodes a lysosomal membrane protein. Protein-coding polymorphisms in the TMEM106B gene dramatically alter the age of onset of FTD in individuals with concomitant GRN mutations. TMEM106 polymorphisms also appear to alter the clinical phenotypes of individuals with mutations in C9ORF72, another FTD/ALS-related gene that appears to regulate lysosomal function. Together, these findings strongly suggest the presence of converging molecular pathways that span multiple individual FTD/ALS genes, though the precise number, composition, and biology of such pathways remains unclear.
Research Strategy
A major focus of our lab is to systematically map how loss of function of FTD/ALS genes affects neuronal cell biology. We are using a combination of forward genetic, proteomic and transcriptomic approaches as unbiased discovery approaches to map converging and diverging pathways across multiple FTD/ALS genes in parallel. We perform these mapping studies are in human iPSC-derived neurons, using a newly-developed method that allows us to scalably generate hundreds of millions of neurons. Top pathways identified in our mapping initiatives are further investigated using traditional hypothesis-based cellular, molecular, biochemical, and imaging approaches. We anticipate that identification and pharmacological manipulation of such pathways may be particularly fruitful for development of disease modifying therapies.
Lab Members
Current Lab Members
Lab Alumni
- Rajan Patel - MD student, Baylor College of Medicine
- Connor Ludwig - PhD student, Stanford
- Robert Chen - MD/PhD student, Washington University School of Medicine
- Shannon Leslie - PhD student, Yale
- Ali Taubes - PhD student, UCSF
Join the Ward Lab
We are always on the lookout for exceptional individuals to join our team, and a postdoctoral position in cell biology and neurodegenerative diseases is currently available in our lab. Candidates should have a Ph.D., M.D. or equivalent degree, less than 4 years of post-doctoral experience, and expertise in cell biology, molecular biology, biochemistry, microscopy. Additional skills in bioinformatics, programming, and/or stem cell biology are preferred. Candidates should have excellent writing and communication skills, and an outstanding publication record.
To apply: Interested candidates should send a cover letter, curriculum vitae, bibliography, and contact information of three references to Michael Ward.
Selected Publications
Select publications are highlighted below. For full list, please see PubMed or Google Scholar.
- Caldecott K*, Ward ME*, Nussenzweig A*. Neurological Disease and ‘Programmed’ DNA breakage. (In Press) Nature Genetics (*co-corresponding authors).
- Brown A, Wilkins O, Keuss M, Hill S, Zanovello M, Colleen Lee W, Lee F, Masino L, Qi Y, Bryce-Smith S, Bamptom A, Gat A, Phatnani H, Schiavo G, Fischer E, Raj T, Secrier M, Lashley Tm, Ule J, Buratti E, Humphrey J, Ward ME*, Fratta P. TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. (2022) Nature 603, 131-137. (*co-corresponding authors)
- Ramos D, Skarnes WC, Singleton A, Cookson M*, Ward ME*. Tackling neurodegenerative diseases with genomic engineering: A new stem cell initiative from the NIH. (2021) Neuron (*co-corresponding authors).
- Wu W, Hill SE, Nathan WJ, Paiano J, Callen E, Wang D, Shinoda K, van Wietmarschen N, Colón-Mercado JM, Zong D, De Pace R, Shih HY, Coon S, Parsadanian M, Pavani R, Hanzlikova H, Park S, Jung SK, McHugh PJ, Canela A, Chen C, Casellas R, Caldecott KW*, Ward ME*, Nussenzweig A*. Neuronal enhancers are hotspots for DNA single-strand break repair. (2021) PMID: 33767446; Nature (*co-corresponding authors)
- Fernandopulle M, Lippincott-Schwartz J* and Ward ME*. (from the cover) RNA transport and local translation in neurodevelopmental and neurodegenerative disease. PMID: 33510479 (2021) Nature Neuroscience (*co-corresponding authors)
- Liao YC, Fernandopulle M, Wang G, Choi H, Hao L, Drerup C, Qamar S, Nixon-Abell J, Shen Y, Meadows W, Vendruscolo M, Knowles T, Nelson M, Czekalska M, Musteikyte G, Patel R, Stephens C, Pasolli A, Forrest L, St George-Hyslop P, Lippincott-Schwartz J* and Ward ME*. RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether. (2019). PMID: 31539493. Cell (*co-corresponding authors), (F1000Prime Recommended).
- Tian R, Gachechiladze MA, Ludwig CH, Laurie MT, Hong JY, Nathaniel D, Prabhu AV, Fernandopulle MS, Patel R, Abshari M, Ward ME* and Kampmann M*. (from the cover) CRISPR Interference-Based Platform for Multimodal Genetic Screens in Human iPSC-Derived Neurons. (2019). PMID: 31422865; Neuron (*co-corresponding authors).