Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington's Disease: Insights from In Vitro and In Vivo Models

Abstract

Huntington's disease (HD) is an autosomal dominant disorder caused by an expansion in the trinucleotide CAG repeat in exon-1 in the huntingtin gene, located on chromosome 4. When the number of trinucleotide CAG exceeds 40 repeats, disease invariably is manifested, characterized by motor, cognitive, and psychiatric symptoms. The huntingtin (Htt) protein and its mutant form (mutant huntingtin, mHtt) are ubiquitously expressed but although multiple brain regions are affected, the most vulnerable brain region is the striatum. Striatal medium-sized spiny neurons (MSNs) preferentially degenerate, followed by the cortical pyramidal neurons located in layers V and VI. Proposed HD pathogenic mechanisms include, but are not restricted to, excitotoxicity, neurotrophic support deficits, collapse of the protein degradation mechanisms, mitochondrial dysfunction, transcriptional alterations, and disorders of myelin. Studies performed in cell type-specific and regionally selective HD mouse models implicate both MSN cell-autonomous properties and cell-cell interactions, particularly corticostriatal but also with non-neuronal cell types. Here, we review the intrinsic properties of MSNs that contribute to their selective vulnerability and in addition, we discuss how astrocytes, microglia, and oligodendrocytes, together with aberrant corticostriatal connectivity, contribute to HD pathophysiology. In addition, mHtt causes cell-autonomous dysfunction in cell types other than MSNs. These findings have implications in terms of therapeutic strategies aimed at preventing neuronal dysfunction and degeneration.

Deficits in coordinated neuronal activity and network topology are striatal hallmarks in Huntington’s disease

“…We provide evidence that striatal circuits have a decreased capacity to transmit information and are more segregated, while individual neuronal activity is preserved. Our data in isolated cultures support the idea that fundamental striatal network deficiencies in HD might be attributed to cellautonomous mechanism of mHtt within the striatum [40], in addition to the described aberrant striatal afferences [9,38].…”

Targeting microglia L‐type voltage‐dependent calcium channels for the treatment of central nervous system disorders

“…Microglia are involved in HD pathology, although relatively few studies have examined their role closely (Creus-Muncunill & Ehrlich, 2019;Möller, 2010). Microglia in HD contain mHTT inclusions (Simmons et al, 2007) but the expression of mHTT in microglia is neither necessary nor sufficient to cause an HD phenotype (Petkau et al, 2019) despite inducing pro-inflammatory gene expression in microglia (Crotti et al, 2014).…”

Repeat Expansion Disorders: Mechanisms and Therapeutics

“…Maiuri et al describe the emerging importance of DNA repair mechanisms in HD and other repeat expansion disorders [13]. Creus-Muncunill and Ehrlich review the detailed and elegant studies directed at understanding the cellautonomous and non-autonomous pathogenic mechanisms in HD [14]. Naphade et al describe the rapid progress using human patient-induced pluripotent stem cells to model HD and other polyQ diseases [15].…”