Huntington's disease (HD) is a fatal neurodegenerative disease caused by mutations introducing an extended stretch of poly-glutamines (poly-Q) at the N-terminus of huntingtin (Htt). A widely accepted, yet unproven, hypothesis is that HD is caused by gain-of-function, toxic effects of mutant Htt protein. In recent years, dominant negative loss-of-function effects of poly-Q mutations have also emerged as drivers of disease pathophysiology. However, despite what is known about pathophysiology of mutant Htt, the functions of wildtype (WT) Htt are still largely unknown. Astrocytes, the major glial cells of the brain, secrete synaptogenic thrombospondin family proteins to initiate synapse formation. Thrombospondin induces synaptogenesis by binding to a neuronal receptor, the gabapentin receptor ?2?-1. In our preliminary experiments, we found that ?2?-1 interacts with huntingtin and this interaction is impaired in the presence of poly-Q expansions. Early synaptic problems in the excitatory cortical and striatal connections have been reported in HD, but whether huntingtin played a role in synaptic connectivity was unknown. By conditionally silencing Htt in the mouse cortex we showed that huntingtin controls synapse formation and maturation within cortical and striatal circuits. Moreover, by using an HD mouse model, we found that this function of huntingtin is lost when the pathogenic poly-glutamine mutation is present. Based on these findings, here we will test the hypotheses that huntingtin controls synaptic connectivity through its interaction with ?2?-1, and that the impairment of this interaction in the presence of the disease-causing poly-Q mutations leads to detrimental errors in synaptic connectivity. The loss-of-function effects of mutant Htt during development may be important for driving the disease onset and could underlie prodromal neurological symptoms of HD. Therefore, understanding the function of WT Htt in synaptic development may enable us to find ways to correct the developmental errors in the cortical and striatal circuits of mutant Huntingtin carriers. This approach could therefore lead to the prevention of disease onset or greatly diminished disease progression, allowing HD patients to live full, healthy lives.

Public Health Relevance

Huntington's Disease (HD) is the most common genetic disorder that causes abnormal involuntary writhing movements due to progressive neurodegeneration that takes place in the striatum of the affected individuals. Uncovering the cellular and molecular mechanisms governed by Htt is crucial to understand the pathophysiology of HD. By elucidating the roles of Htt in the formation and function of synaptic connections, we will gain the much-needed new insight into the progressive synaptic dysfunction seen in HD. Such an understanding has the potential to lead to the development of innovative approaches to cure HD.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Miller, Daniel L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
E, Lezi; Zhou, Ting; Koh, Sehwon et al. (2018) An Antimicrobial Peptide and Its Neuronal Receptor Regulate Dendrite Degeneration in Aging and Infection. Neuron 97:125-138.e5
Risher, W Christopher; Kim, Namsoo; Koh, Sehwon et al. (2018) Thrombospondin receptor ?2?-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1. J Cell Biol 217:3747-3765
Gomez-Pastor, Rocio; Burchfiel, Eileen T; Neef, Daniel W et al. (2017) Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease. Nat Commun 8:14405
Stogsdill, Jeff A; Eroglu, Cagla (2017) The interplay between neurons and glia in synapse development and plasticity. Curr Opin Neurobiol 42:1-8
Allen, Nicola J; Eroglu, Cagla (2017) Cell Biology of Astrocyte-Synapse Interactions. Neuron 96:697-708
Baldwin, Katherine T; Eroglu, Cagla (2017) Molecular mechanisms of astrocyte-induced synaptogenesis. Curr Opin Neurobiol 45:113-120
Park, John; Yu, Yanhui Peter; Zhou, Chun-Yi et al. (2016) Central Mechanisms Mediating Thrombospondin-4-induced Pain States. J Biol Chem 291:13335-48