The striatum is the largest component of the basal ganglia, and its degeneration is the cause for motor dysfunction associated with Huntington's disease (HD), a dominantly inherited neurodegenerative disorder caused by the expansion of a polyglutamine tract at the N-terminus of the huntingtin (htt) protein. In addition, it has been implicated in several developmental disorders. The vast majority of striatal neurons are medium- sized spiny neurons (MSNs) with the rest being interneurons. MSNs are divided into two populations: those expressing the dopamine receptor D2 (DRD2) in the indirect pathway and those expressing the dopamine receptor D1a (DRD1a) in the direct pathway. Studies have demonstrated that MSNs are born in the lateral ganglionic eminence (LGE);however, it remains largely unknown how the further development of MSNs is regulated. It also remains unclear how a mutation in the ubiquitously expressed htt causes selective and severe neuronal loss in the striatum and to a lesser extent in the cortex and why DRD2 MSNs are the most affected cells in the striata of HD patients. We hypothesize that anterogradely transported brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) control survival and dendritic arborization of newborn MSNs. We further hypothesize that local synthesis of mutant htt in dendrites plays a key role in the HD pathogenesis and that differential expression of TrkB (the receptor for BDNF) in MSNs contributes to selective degeneration in HD. These hypotheses are based on strong evidence from our previous studies. This research project has four specific aims.
Specific Aim 1 is to investigate whether BDNF and NT3 transported anterogradely from nigrostriatal dopaminergic neurons support the survival of newborn MSNs by deleting the BDNF or Nt3 gene in dopaminergic neurons.
Specific Aim 2 is to determine whether BDNF is required for the development of dendritic arborization of DRD2 MSNs by using cultured striatal neurons and mutant mice where the TrkB gene is deleted in DRD2-expressing cells.
Specific Aim 3 is to investigate whether huntingtin transcripts are transported to dendrites for local translation and whether dendritic synthesis of mutant huntingtin contributes to the HD pathogenesis in cultured neurons.
Specific Aim 4 is to examine whether the preferential TrkB expression in DRD2 MSNs contributes to selective degeneration in HD by deleting the TrkB gene in DRD2-expressing cells of adult wild-type and HD mice. Results from this proposed research will provide insights into the regulation of striatal development and the pathogenesis of HD.

Public Health Relevance

The striatum is the largest component of the basal ganglia and is associated with several neurological disorders, including Huntington's disease (HD). Findings from this proposed research will provide important information as to HD pathogenesis and cell replacement therapy for striatum-based diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050596-07
Application #
8300794
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Sutherland, Margaret L
Project Start
2004-12-01
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
7
Fiscal Year
2012
Total Cost
$333,207
Indirect Cost
$114,457
Name
Georgetown University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Vanevski, Filip; Xu, Baoji (2015) HuD interacts with Bdnf mRNA and is essential for activity-induced BDNF synthesis in dendrites. PLoS One 10:e0117264
Xie, Keqiang; Masuho, Ikuo; Shih, Chien-Cheng et al. (2015) Stable G protein-effector complexes in striatal neurons: mechanism of assembly and role in neurotransmitter signaling. Elife 4:
Baydyuk, Maryna; Xu, Baoji (2014) BDNF signaling and survival of striatal neurons. Front Cell Neurosci 8:254
Unterwald, Ellen M; Page, Michelle E; Brown, Timothy B et al. (2013) Behavioral and transcriptome alterations in male and female mice with postnatal deletion of TrkB in dorsal striatal medium spiny neurons. Mol Neurodegener 8:47
Orefice, Lauren L; Waterhouse, Emily G; Partridge, John G et al. (2013) Distinct roles for somatically and dendritically synthesized brain-derived neurotrophic factor in morphogenesis of dendritic spines. J Neurosci 33:11618-32
Baydyuk, Maryna; Xie, Yuxiang; Tessarollo, Lino et al. (2013) Midbrain-derived neurotrophins support survival of immature striatal projection neurons. J Neurosci 33:3363-9
Xu, Baoji (2013) BDNF (I)rising from exercise. Cell Metab 18:612-4
Waterhouse, Emily G; An, Juan Ji; Orefice, Lauren L et al. (2012) BDNF promotes differentiation and maturation of adult-born neurons through GABAergic transmission. J Neurosci 32:14318-30
Kaneko, Megumi; Xie, Yuxiang; An, Juan Ji et al. (2012) Dendritic BDNF synthesis is required for late-phase spine maturation and recovery of cortical responses following sensory deprivation. J Neurosci 32:4790-802
Liao, Guey-Ying; An, Juan Ji; Gharami, Kusumika et al. (2012) Dendritically targeted Bdnf mRNA is essential for energy balance and response to leptin. Nat Med 18:564-71

Showing the most recent 10 out of 21 publications