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

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Huntington disease (HD) is an autosomal dominant neurodegenerative disorder of the central nervous system (CNS) that is defined by a CAG expansion in exon 1 of the huntingtin gene leading to the production of mutant huntingtin (mHTT)1. Over time, this protein accumulates in neurons, causing dysfunction and death, which leads to a progressive disorder of movement and cognition along with psychiatric and metabolic problems. However, mHTT is not always found inside cellular compartments, but is also present outside the cell boundary, notably in the cerebrospinal fluid, plasma, and extracellular matrix.2 The HD gene product is further expressed outside the CNS, leading to peripheral pathology.7 In theory, mHTT aggregates should be found in every tissue and cell type of the body, but their presence/location within the spinal cord and their pathological significance at this site have not been investigated, and this includes effects on the blood–spinal cord barrier (BSCB).
In this respect, we and others have reported that there are changes in cerebrovascular vessel density in patients with HD as well as in transgenic mouse models of the disease,9 which are further accompanied by measurable blood vessel leakage. More recent reports have established that dysregulation in mRNAs of tight junction proteins, corresponding to increased permeability of blood vessels, actually precedes the manifestation of pathological hallmarks of the R6/2 mouse model of the disease,11 suggesting that blood–brain barrier (BBB) impairments are not a just consequence, but an initial feature of disease pathology. This is further supported by a recent study showing that human induced pluripotent stem cell (iPSC)‐derived brain microvascular endothelial cells (BMECs) from HD patients have increased angiogenic potential as well as impaired barrier functions.12
The BSCB is very similar to the BBB,13 but there are still some differences between them. For example, zona occludens‐1 (ZO‐1) and occludin expression are decreased in the BSCB,15 making it more permeable.16 Furthermore, it has been reported that the BSCB plays a key role in the etiology of various diseases that show major pathology within the spinal cord, such as multiple sclerosis17 and amyotrophic lateral sclerosis (ALS).16 In this latter condition, it has been shown that the BSCB is characterized by significantly reduced expression of tight junction proteins such as ZO‐1, vascular endothelial cadherin (VE‐cadherin), junctional adhesion molecule‐1 (JAM‐1), occludin, and claudin‐5 as well as a more leaky microvasculature,18 as evidenced by increased extravasation of erythrocytes and plasma proteins in the spinal cord.19
Based on this, we undertook an exhaustive postmortem study to investigate the distribution, frequency, and specific localization of mHTT aggregates within the spinal cord of patients with HD and their relationship to vascular networks, BSCB leakage, and function. We found mHTT aggregates in the spinal cord of HD patients with evidence of abnormalities and increased leakage of the BSCB.

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