Abstract
Huntington’s disease (HD) is an autosomal dominant trinucleotide repeat disorder characterized by choreiform movements, dystonia and striatal neuronal loss. Amongst multiple cellular processes, abnormal neurotransmitter signalling and decreased trophic support from glutamatergic cortical afferents are major mechanisms underlying striatal degeneration. Recent work suggests that the thalamostriatal (TS) system, another major source of glutamatergic input, is abnormal in HD although its phenotypical significance is unknown. We hypothesized that TS dysfunction plays an important role in generating motor symptoms and contributes to degeneration of striatal neuronal subtypes. Our results using the R6/2 mouse model of HD indicate that neurons of the parafascicular nucleus (PF), the main source of TS afferents, degenerate at an early stage. PF lesions performed prior to motor dysfunction or striatal degeneration result in an accelerated dystonic phenotype and are associated with premature loss of cholinergic interneurons. The progressive loss of striatal medium spiny neurons and parvalbumin-positive interneurons observed in R6/2 mice is unaltered by PF lesions. Early striatal cholinergic ablation using a mitochondrial immunotoxin provides evidence for increased cholinergic vulnerability to cellular energy failure in R6/2 mice, and worsens the dystonic phenotype. The TS system therefore contributes to trophic support of striatal interneuron subtypes in the presence of neurodegenerative stress, and TS deafferentation may be a novel cell non-autonomous mechanism contributing to the pathogenesis of HD. Furthermore, behavioural experiments demonstrate that the TS system and striatal cholinergic interneurons are key motor-network structures involved in the pathogenesis of dystonia. This work suggests that treatments aimed at rescuing the TS system may preserve important elements of striatal structure and function and provide symptomatic relief in HD.
Highlights
Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder characterized by choreiform movements, dystonia and psychiatric symptoms [1, 2]
The parafascicular nucleus (PF) degenerates in the R6/2 model of HD To determine if the PF is susceptible to degeneration in HD, we quantified neuron numbers and soma size in the PF throughout the lifespan of the R6/2 mouse model using unbiased stereology
Application of the nucleator probe demonstrated that soma size of PF neurons was reduced in R6/2 mice compared to WT at 9 and 13 weeks (Fig. 1a, w (43) = 0.954, p = 0.086, F(GenotypeXTime)4,33 = 1.45, p = 0.24, F(Time)4,33 = 3.85, p = 0.01, F(Genotype)1,33 = 8.46, p = 0.006, post hoc comparison: 9 wks p = 0.03 and 13 wks p = 0.01)
Summary
Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder characterized by choreiform movements, dystonia and psychiatric symptoms [1, 2]. Despite ubiquitous expression of mhtt, medium spiny projection neurons (MSNs) of the striatum are a major target for degeneration [2]. Interneurons, which comprise a small proportion of all striatal neurons, Loss of afferent-mediated trophic support contributes to neuronal loss in common neurodegenerative diseases, including Alzheimer’s disease [17, 18] and Parkinson’s disease [19,20,21]. Trophic support from the major glutamatergic striatal afferent systems may play an important role in Crevier-Sorbo et al Acta Neuropathologica Communications. Recent MRI studies indicate that the thalamus undergoes significant atrophy in early disease [23]. Post-mortem analysis indicates that the posterior intralaminar thalamus, or centromedian-parafascicular (CM-PF) complex, is an important target for degeneration in HD [24]
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