The Lloyd laboratory studies the molecular and cellular mechanisms underlying neurodegenerative diseases of the peripheral nervous system. We focus primarily on three diseases:
1. Amyotrophic Lateral Sclerosis (ALS) is a rapidly fatal disease of motor neurons. We primarily use simple invertebrate models of familial forms of ALS to investigate how genetic mutations alter motor neuron structure, function, and survival. Our studies of a Drosophila model of ALS caused by expression of a GGGGCC hexanucleotide repeat expansion led to the discovery that these repeats bind and inhibit a protein called RanGAP, a master regulator of nucleocytoplasmic transport. We are currently investigating how these alterations in nuclear transport cause neurodegeneration. Our current model is that inhibition of nuclear import leads to a toxic accumulation of ubiquitinated protein aggregates in the cytoplasm. These aggregates are insufficiently cleared by autophagy, leading to inhibition of the proteasome and ER stress. Importantly, pharmacologic or genetic inhibition of nuclear export suppresses GGGGCC-mediated neurodegeneration, suggesting a possible new therapeutic strategy for ALS. Importantly, in collaboration with Jeff Rothstein’s laboratory, we have validated RanGAP pathology and nuclear transport disruption in iPS neurons derived from ALS patients and in patient brain tissue. Studying multiple genetic models of ALS (eg c9orf72, FUS, TDP43), including performing unbiased screens, allows us to find common pathogenic pathways that underlie ALS.
2. Charcot-Marie-Tooth (CMT) disease (also known as Hereditary Sensorimotor Neuropathy) is one of the most common inherited neurological diseases and can be caused by mutations in over 100 different genes. We focus on CMT type 2D (caused by mutations in the TRPV4 channel), CMT4J (caused by mutations in the phosphoinositide phosphatase FIG4), and HMN7B (Hereditary Motor Neuropathy type 7B caused by mutations in the p150/Glued subunit of Dynactin). These hereditary motor neuropathies all have in common a disruption of vesicular trafficking and/or axonal transport. We use a variety of live imaging and electrophysiological techniques to investigate pathophysiology of organelle transport and synaptic transmission defects in these models.
3. Inclusion Body Myositis (IBM) is the most common muscle disease in adults over the age of 50, and causes progressive muscle degeneration and weakness. Although inflammation is observed on biopsy, patients fail to respond to immunosuppressive treatment, and there are no good animal models of this disease. The Johns Hopkins Myositis Center has one of the largest collections of myositis patient samples, and we use genetic, proteomic, and pathologic approaches to understand the pathogenesis of this disease. Intriguingly, there is genetic and pathologic overlap of IBM with ALS, suggesting shared pathobiology.
- Wong MY, Zhou C, Shakiryanova D, Lloyd TE, Deitcher DL, and Levitan ES. Neuropeptide Delivery to Synapses by Long Range Vesicle Circulation and Sporadic Capture. Cell. 2012; 148(5): 1029-38
- Lloyd TE *, Machamer J, O’Hara K, Kim JH, Collins SE, Wong MY, Sahin B, Imlach W, Yang Y, Levitan ES, McCabe BD, Kolodkin AL.* The p150Glued CAP-Gly Domain Regulates Initiation of Retrograde Transport at Synaptic Termini. Neuron. 2012; 74, 344-360.
- Machamer JB, Collins SE, Lloyd TE*. The ALS gene FUS regulates synaptic transmission at the Drosophila neuromuscular junction. Human Molecular Genetics. 2014; 23(14)3810-22.
- Lloyd TE*, Mammen AL, Amato AA, Weiss MD, Needham M, Greenberg SA.* Evaluation and Construction of Diagnostic Criteria for Inclusion Body Myositis. Neurology. 2014; 83:426-33.
- Herrmann DN, Horvath R, Sowden JE, Gonzales M, Sanchez-Mejias A, Guan Z, Whittaker RG, Almodovar JL, Lane M, Bansagi B, Pyle A, Boczonadi V, Lochmüller H, Griffin H, Chinnery PF, Lloyd TE, Littleton JT, and Zuchner S. Synaptotagmin 2 Mutations Cause Autosomal-Dominant Form of Lambert-Eaton Myasthenic Syndrome and Nonprogressive Motor Neuropathy. The American Journal of Human Genetics. 2014; 95(3):332-9.