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.
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.
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