Huntington’s disease (HD) is an insidious neurodegenerative disorder caused by trinucleotide repeat expansion in exon 1 of the gene that codes for Huntingtin (mHtt). The pathogenic mechanisms underlying HD remain poorly understood. Studies of HD models have documented numerous developmental impairments during ‘pre- manifest’ HD. Using conditional HD models, the Mehler laboratory team has previously shown that such developmental processes mediate disease pathogenesis. Now, this team provides evidence demonstrating that interneuron neurogenesis is prominently disrupted in mouse models of HD, leading to deficits in the complement of these interneurons within the developing cerebral cortex. Such deficits are of great importance, as studies have shown these lead to permanent changes in cortico-striatal connectivity laying the foundation for cortical hyperexcitability, impaired excitation-inhibition coupling, and striatal excitotoxic stress later in life. Although cortical interneuron deficits have previously been reported in HD cases, their role in HD pathogenesis has never been further interrogated. This application tests the central hypothesis that HD is caused by impairments in the developmental elaboration of selective cortical interneuron subtypes; therefore, prevention of the adverse developmental effects of these interneuron deficits will ameliorate or even prevent disease occurrence. This hypothesis is further supported by preliminary data showing that genetic rescue of developing interneurons precludes the onset of characteristic features of HD in BACHD mice: motor coordination deficits, hypomyelination of subcortical white matter tracts and striatal degeneration. Specific Aim 1 (SA1) initially defines whether interneuron progenitor cell supplementation via heterochronic grafts into mutant neonatal pups favorably modifies the occurrence of motor deficits and striatal degeneration, two distinctive traits of HD. This aim also examines whether the role of interneurons in disease progression takes place at the expense of quantitative deficits or through additional factors associated with expression of mutant huntingtin in these cells. SA2 interrogates the interneuron-dependent pathogenic mechanisms mediating HD, focusing on putative modulatory effects of GABA, Reelin and complementary ligand release. Finally, SA3 employs a large array of HD postmortem specimens from two major brain banks to define the role in disease progression of cortical interneuron deficits. This aim also interrogates whether known HD genetic modifiers, including trinucleotide expansion length and/or polymorphisms of DNA damage response genes modulate the extent of interneuron alterations, as well as whether these cells mediate the predictive effects of these genetic modifiers on age at disease onset/progression. Overall, confirmation of the central hypothesis would have substantial implications for the field, as it will provide strong evidence regarding the intersectional roles of interneurons in HD pathogenesis and also define a novel early-stage therapeutic window for preventing HD onset and progression for a neurodegenerative disorder currently lacking substantive and effective therapeutic interventions.
|Effective start/end date||8/1/22 → 7/31/23|
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