Abstract
In recent years, evidence has accumulated to suggest that mutant huntingtin protein (mHTT) can spread into healthy tissue in a prion-like fashion. This theory, however, remains controversial. To fully address this concept and to understand the possible consequences of mHTT spreading to Huntington’s disease pathology, we investigated the effects of exogenous human fibrillar mHTT (Q48) and huntingtin (HTT) (Q25) N-terminal fragments in three cellular models and three distinct animal paradigms. For in vitro experiments, human neuronal cells [induced pluripotent stem cell-derived GABA neurons (iGABA) and (SH-SY5Y)] as well as human THP1-derived macrophages, were incubated with recombinant mHTT fibrils. Recombinant mHTT and HTT fibrils were taken up by all cell types, inducing cell morphology changes and death. Variations in HTT aggregation were further observed following incubation with fibrils in both THP1 and SH-SY5Y cells. For in vivo experiments, adult wild-type (WT) mice received a unilateral intracerebral cortical injection and R6/2 and WT pups were administered fibrils via bilateral intraventricular injections. In both protocols, the injection of Q48 fibrils resulted in cognitive deficits and increased anxiety-like behavior. Post-mortem analysis of adult WT mice indicated that most fibrils had been degraded/cleared from the brain by 14 months post-surgery. Despite the absence of fibrils at these later time points, a change in the staining pattern of endogenous HTT was detected. A similar change was revealed in post-mortem analysis of the R6/2 mice. These effects were specific to central administration of fibrils, as mice receiving intravenous injections were not characterized by behavioral changes. In fact, peripheral administration resulted in an immune response mounting against the fibrils. Together, the in vitro and in vivo data indicate that exogenously administered mHTT is capable of both causing and exacerbating disease pathology.
Highlights
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that typically progresses to death over 10–30 years [51]
After confirming the presence of fibrils, a dose response curve was performed in a human neuroblastoma-derived cell line (SH-SY5Y) and 0.005 μg/μL was selected as the working concentration (Online Resource 1c)
Cells exposed to Q48 fibrils had significantly more puncta per cell than did cells exposed to Q25 (Fig. 1d)
Summary
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that typically progresses to death over 10–30 years [51]. During the pre-manifest phase, subtle changes in personality, cognition and motor control can be observed which, over time, lead to diagnosis based on motor features of the condition. HD patients exhibit progressive cognitive impairments that impact activities of daily living along with psychiatric disturbances that can evolve to frank psychosis and a worsening movement disorder. Patients become demented and bedbound [24, 51, 54, 59]. The classic neuropathological feature is a massive atrophy of the caudate and putamen which results from neuronal dysfunction and loss, especially of the medium spiny projection neurons. Progressive neuronal loss and atrophy are observed
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