Mutant huntingtin protein expression and blood–spinal cord barrier dysfunction in huntington disease

Sciacca, Giacomo; Cicchetti, Francesca

doi:10.1002/ana.25107

Cited by 18 publications

(15 citation statements)

References 33 publications

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“…In HD, the expanded huntingtin proteins form protein aggregates in neurons, and basal ganglia, caudate nucleus, and putamen are among the first brain areas to be affected. Furthermore, blood-spinal cord barrier leakage is observed in HD patients [120]. Recently, it has been noted that brain pericytes become activated early in the HD disease process [118], and HD is associated with impaired BBB function and decreased PDGF-b mRNA expression in pericytes [119].…”

Section: Neurodegenerative Diseases and The Brain Vasculature-an Emermentioning

confidence: 99%

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Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

2019

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Neurodegenerative and cerebrovascular diseases cause considerable human suffering, and therapy options for these two disease categories are limited or non-existing. It is an emerging notion that neurodegenerative and cerebrovascular diseases are linked in several ways, and in this review, we discuss the current status regarding vascular dysregulation in neurodegenerative disease, and conversely, how cerebrovascular diseases are associated with central nervous system (CNS) degeneration and dysfunction. The emerging links between neurodegenerative and cerebrovascular diseases are reviewed with a particular focus on pericytes-important cells that ensheath the endothelium in the microvasculature and which are pivotal for blood-brain barrier function and cerebral blood flow. Finally, we address how novel molecular and cellular insights into pericytes and other vascular cell types may open new avenues for diagnosis and therapy development for these important diseases.

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Section: Neurodegenerative Diseases and The Brain Vasculature-an Emermentioning

confidence: 99%

“…Recently, it has been noted that brain pericytes become activated early in the HD disease process [118], and HD is associated with impaired BBB function and decreased PDGF-b mRNA expression in pericytes [119]. Furthermore, blood-spinal cord barrier leakage is observed in HD patients [120].…”

Section: Neurodegenerative Diseases and The Brain Vasculature-an Emermentioning

confidence: 99%

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

2019

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“…Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by the pathological expansion of CAG repeats (> 36) in the rst exon of the HD gene encoding huntingtin (Htt) [1][2][3][4][5][6][7][8]. Neuropathologically, the neuronal loss occurs primarily in the striatum and the cortex in the early stages of HD.…”

Section: Introductionmentioning

confidence: 99%

“…Neuropathologically, the neuronal loss occurs primarily in the striatum and the cortex in the early stages of HD. However, other brain regions, such as the hippocampus, hypothalamus, brainstem, and spinal cord, are also affected in advanced stages [2][3][4][5][6]9]. HD symptoms occur usually in mid-life, comprising movement, cognitive and psychiatric impairments inexorably progressing to death within two decades [1,7].…”

Section: Introductionmentioning

confidence: 99%

“…Dual-luciferase reporter gene assay BHK cells were seeded in 12-well tissue culture plates at 2 ×105 per well in 1ml of Opti-MEM (Invitrogen) at 24 h before transfection. For the detection of targeting relationship of Sp1 and ZnT3, pEBGN-Sp1 was co-transfected with reporter plasmids pGL3-ZnT3 (-283 ~ + 10), pGL3-ZnT3 (-193 ~ + 10), or pGL3-ZnT3 (-171 ~ + 10), respectively, into BHK cells.…”

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confidence: 99%

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Mutant huntingtin reduces vesicular zinc level by inhibiting the binding of Sp1 to ZnT3 promoter

Niu

Yang

Wang

et al. 2020

Preprint

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Background Synaptic dysfunction caused by mutant huntingtin greatly contributes to Huntington’s disease (HD) pathogenesis. HD patients show cognitive impairment as well as uncontrolled movements. Vesicular zinc is closely linked to modulating synaptic transmission and maintaining cognitive ability. However, whether does mutant huntingtin affect zinc homeostasis in the brain or not? This will be of great significance for further revealing the pathogenesis of HD. Methods N171-HD82Q transgenic mice and cultured BHK cells expressing N-terminal mutant huntingtin fragment containing 160 glutamines (160Q BHK cells) were used to investigate the effect of mutant huntingtin on zinc homeostasis and its molecular mechanisms. Results Herein, we have demonstrated that the density of synaptic vesicular zinc decreases in the cortex, striatum and hippocampus of N171-82Q mice. Given that vesicular zinc concentration depends on the abundance of zinc transporter 3 (ZnT3) on the membrane of synaptic vesicles, ZnT3 expression is detected in the brain of N171-82Q mice and 160Q BHK cells. Mutant huntingtin leads to a dramatical decrease in ZnT3 mRNA and protein levels in the three brain regions of these mice aged from 14 to 20 weeks. Significantly, Sp1 activates ZnT3 transcription via its binding to the GC boxes in ZnT3 promoter. Nevertheless, mutant huntingtin inhibits the binding of Sp1 to the promoter of ZnT3 gene and down-regulates ZnT3 expression. Furthermore, the overexpression of Sp1 ameliorates inhibition of ZnT3 gene transcription by mutant huntingtin. Conclusions Collectively, this first study to reveal a significant loss of synaptic vesicular zinc and ZnT3 expression caused by mutant huntingtin in the early stage of HD. Our findings have revealed the molecular mechanism underlying this change. Mutant huntingtin inhibits the binding of Sp1 to ZnT3 gene promoter to reduce ZnT3 expression. The imbalance of vesicular zinc homeostasis may be closely associated with synaptic dysfunction and cognitive deficits in HD. This work sheds novel mechanistic insights into the pathogenesis of HD and promises a potential therapeutic strategy for HD.

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Dysregulated Brain Cholesterol Metabolism Is Linked to Neuroinflammation in Huntington's Disease

et al. 2020

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Huntington's disease is an autosomal‐dominant, neurodegenerative disorder caused by a CAG repeat expansion in exon‐1 of the huntingtin gene. Alterations in cholesterol metabolism and distribution have been reported in Huntington's disease, including abnormal interactions between mutant huntingtin and sterol regulatory element‐binding proteins, decreased levels of apolipoprotein E/cholesterol/low‐density lipoprotein receptor complexes, and alterations in the synthesis of ATP‐binding cassette transporter A1. Plasma levels of 24S‐hydroxycholestrol, a key intermediary in cholesterol metabolism and a possible marker in neurodegenerative diseases, decreased proportionally to the degree of caudate nucleus atrophy. The interaction of mutant huntingtin with sterol regulatory element‐binding proteins is of particular interest given that sterol regulatory element‐binding proteins play a dual role: They take part in lipid and cholesterol metabolism, but also in the inflammatory response that induces immune cell migration as well as toxic effects, particularly in astrocytes. This work summarizes current evidence on the metabolic and immune implications of sterol regulatory element‐binding protein dysregulation in Huntington's disease, highlighting the potential use of drugs that modulate these alterations. © 2020 International Parkinson and Movement Disorder Society

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Mutant huntingtin protein expression and blood–spinal cord barrier dysfunction in huntington disease

Cited by 18 publications

References 33 publications

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

Mutant huntingtin reduces vesicular zinc level by inhibiting the binding of Sp1 to ZnT3 promoter

Dysregulated Brain Cholesterol Metabolism Is Linked to Neuroinflammation in Huntington's Disease

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