Striatal Interneurons in Transgenic Nonhuman Primate Model of Huntington’s Disease

Abstract

Huntington’s disease is an autosomal dominant neurodegenerative disorder associated with progressive motor and cognitive impairments, and the expansion of a cysteine-adenine-guanine trinucleotide (polyglutamine) repeats in exon one of the human huntingtin gene. The pathology of the disease is characterized by a profound degeneration of striatal GABAergic projection neurons with relative sparing of interneurons accompanied with astrogliosis. Here, we describe the striatal pathology in two genotypically different transgenic HD monkeys that exhibit degrees of disease progression that resembled those seen in juvenile- (rHD1) and adult-onset (rHD7) HD. The caudate nucleus and putamen underwent severe neuronal loss in both animals, while the striatal volume was reduced only in rHD1, the most severely affected monkey. The number of GABAergic (calretinin- and parvalbumin-positive) and cholinergic interneurons was also reduced in most striatal regions of these two monkeys, but to variable degrees. Overall, the density of interneurons was increased in rHD1, but not in rHD7, suggesting a relative sparing of interneurons over projection neurons in the striatum of the most affected HD monkey. The neuropil of both the caudate nucleus and putamen was invaded with reactive astrocytes in rHD1, while astrogliosis was much less severe in rHD7 and absent from control. Combined with behavioral data collected from these monkeys, our findings further demonstrate that transgenic HD monkeys share similar disease patterns with HD patients, making them a highly reliable preclinical HD animal model.

Progressive Polyglutamine Repeat Expansion in Peripheral Blood Cells and Sperm of Transgenic Huntington’s Disease Monkeys

“…A longitudinal study in a Venezuelan cohort reported similar findings, with very little instability in HD patients' lymphoblastoid cells over ten years or in sperm over two years [18]. Here, we investigated CAG repeat instability by measuring CAG repeat length in lymphocytes and sperm collected throughout the nine-year lifespan of a group of transgenic HD monkeys, which has been shown to resemble human disease progression based on clinical measurements including behavioral and cognitive declines and progressive anatomical changes including regional brain atrophy and alterations in white matter [20][21][22][23][24][25][26][27].…”

Recurrent Implication of Striatal Cholinergic Interneurons in a Range of Neurodevelopmental, Neurodegenerative, and Neuropsychiatric Disorders

“…HD is a heritable, progressive neurodegenerative disorder characterized by involuntary movements, psychiatric disturbances, and cognitive decline [ 247 ]. The pathophysiology of HD is marked by the death of striatal MSNs [ 248 , 249 ]. Striatal ChINs are mostly spared from degeneration [ 250 , 251 ], but they still undergo pathophysiological changes that are thought to contribute to the beginning stages of HD [ 252 ].…”

Large Animal Models of Huntington’s Disease: What We Have Learned and Where We Need to Go Next

“…Similarly, diffusion tensor imaging (DTI) analysis suggested microstructural changes in several white matter tracts throughout the brain [ 69 ]. Cell counts in two animals verified a reduction of both projection neurons and interneurons in the caudate and putamen, with elevated astrocyte number, that was HTT fragment length dependent [ 70 ]. Additionally, these two animals showed varying levels of mHTT aggregates.…”