Disruption of the nuclear membrane by perinuclear inclusions of mutant huntingtin causes cell-cycle re-entry and striatal cell death in mouse and cell models of Huntington's disease

Abstract

Accumulation of N-terminal fragments of mutant huntingtin (mHTT) in the cytoplasm, nuclei and axons of neurons is a hallmark of Huntington's disease (HD), although how these fragments negatively impact neurons remains unclear. We followed the distribution of mHTT in the striata of transgenic R6/2-J2 HD mice as their motor function declined. The fraction of cells with diffuse, perinuclear or intranuclear mHTT changed in parallel with decreasing motor function. In transgenic mice, medium spiny neurons (MSNs) that exhibited perinuclear inclusions expressed cell-cycle markers typically not seen in the striata of normal mice, and these cells are preferentially lost as disease progresses. Electron microscopy reveals that perinuclear inclusions disrupt the nuclear envelope. The progression of perinuclear inclusions being accompanied by cell-cycle activation and culminating in cell death was also observed in 1° cortical neurons. These observations provide a strong correlation between the subcellular location of mHTT, disruption of the nucleus, re-entry into the cell-cycle and eventual neuronal death. They also highlight the fact that the subcellular distribution of mHTT is highly dynamic such that the distribution of mHTT observed depends greatly on the stage of the disease being examined.

Long Term Aggresome Accumulation Leads to DNA Damage, p53-dependent Cell Cycle Arrest, and Steric Interference in Mitosis

“…It has been reported that neural stem cells expressing a polyQ expansion protein suffer from impaired lineage restriction, reduced proliferative potential, and enhanced late-stage self-renewal (52), suggesting that polyQ pathology begins very early in the development of neural cells. Cell models expressing aggregation-prone polyQ proteins also experience problems with cell division, such as cell cycle arrest (51) and decreased proliferation (53). Furthermore, neuroimaging has shown that prodromal Huntington disease males have a smaller intracranial volume than controls, suggesting abnormal development in brain tissues expressing mutant Htt (54).…”

Huntingtin exon 1 fibrils feature an interdigitated β-hairpin–based polyglutamine core

“…Htt exon1 is known to misfold and self-assemble via a series of aggregated species, including spherical oligomers, protofibrils, mature amyloid fibrils, and large fibril clusters (3)(4)(5)(6). Although some studies suggested that large inclusions are nontoxic and may be protective (7), recent work also revealed the presence in cells of smaller amyloid aggregates of exon1 that are not visible in normal fluorescence microscopy (8) and specific toxic cellular events triggered by inclusions (9). Despite their potential importance, only limited atomic resolution structural data are available on the fibrillar aggregates that are formed by htt exon1 or other polyQ-based proteins or peptides (10).…”

Huntington’s Disease: Mechanisms of Pathogenesis and Therapeutic Strategies

“…A recent study has suggested that some aggregates that appear to be nuclear may indeed be perinuclear (i.e., cytoplasmic). These perinuclear aggregates have been proposed to be the toxic species, which appear to cause cell death by abnormally activating the cell cycle (Liu et al 2015). This study may resolve some of the controversy about the roles of aggregates in HD, as it appeared that the truly nuclear aggregates were relatively benign, compared with the perinuclear aggregates, and that diffuse mutant huntingtin does not impact cell death.…”