Molecular insights into cortico-striatal miscommunications in Huntington's disease

Abstract

Huntington's disease (HD), a dominantly inherited neurodegenerative disease, is defined by its genetic cause, a CAG-repeat expansion in the HTT gene, its motor and psychiatric symptomology and primary loss of striatal medium spiny neurons (MSNs). However, the molecular mechanisms from genetic lesion to disease phenotype remain largely unclear. Mouse models of HD have been created that exhibit phenotypes partially recapitulating those in the patient, and specifically, cortico-striatal disconnectivity appears to be a shared pathogenic event shared by HD mouse models and patients. Molecular studies have begun to unveil converging molecular and cellular pathogenic mechanisms that may account for cortico-striatal miscommunication in various HD mouse models. Systems biological approaches help to illuminate synaptic molecular networks as a nexus for HD cortio-striatal pathogenesis, and may offer new candidate targets to modify the disease.

Figure 1

Summary of the design and phenotypes seen in several common murine HD models. Reviewed by [12,13]; References for transcriptomic and proteomic changes, [53,59, Yang lab unpublished]. Abbreviations: KI, Knock In; FL, Full Length; RMP, resting membrane potential; sEPSCs, spontaneous Excitatory Post Synaptic Currents; SynNMDA, synaptic NMDA; exSynNMDA, extrasynaptic NMDA; Ctx, cortex; Str, striatum.

Figure 2

Disconnectivity at the cortico-striatal synapse is mediated by presynaptic and postsynaptic changes in gene expression, vesicle trafficking and release, Glutamate-NMDAR signaling, BDNF signaling, and CB1 signaling as well as glial cell dysfunction impinging on these pathways.

Figure 3

Htt interacting proteins are enriched for presynaptic and postsynaptic functions. (A) Experimental design and Venn diagrams of the overlap between Htt interacting proteins and pre-and post-synaptic function. (B) Weighted Gene Correlation Network Analysis (WGCNA) modules describing Htt interactor networks associated with synaptic function. Adapted from [81].

Figure 4

Systems biological analysis of protein and gene interaction networks derived from HD knockin models with varying CAG-repeat lengths (Allelic series), highlights significant changes in both cortical and striatal synapses. (A) Schematic of the experimental design. (B) Three significantly enriched synaptic WGCNA modules, two in the striatum and one in the cortex, showing age and CAG-length dependent down-regulation. (C) Venn diagram and gene lists of significantly enriched synaptic Htt interactors that overlap with genes up- or down-regulated in the striatum of allelic series RNA-seq data. For complete gene lists see Supplemental table. Adapted from [53].