Systemic manifestation and contribution of peripheral tissues to Huntington’s disease pathogenesis

Chuang, Chia-Lung; Demontis, Fabio

doi:10.1016/j.arr.2021.101358

Cited by 37 publications

(22 citation statements)

References 191 publications

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“…However, we did not use enrichment of neural-derived EVs by the L1CAM antibodies as done in other studies in AD and PD [ 60 , 63 ], to keep the isolation protocol simple and reproducible, particularly when two different species were included in our study. In addition, unlike Tau protein and α-synuclein, which have prevalent expression in brain, the HTT is expressed throughout the body and HD affects peripheral organs also [ 83 , 84 ]. Thus, not only the central nervous system, but also other organs can be sources of EVs of interest.…”

Section: Discussionmentioning

confidence: 99%

Huntingtin Co-Isolates with Small Extracellular Vesicles from Blood Plasma of TgHD and KI-HD Pig Models of Huntington’s Disease and Human Blood Plasma

Ananbeh

Novak

Juhás

et al. 2022

IJMS

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(1) Background: Huntington’s disease (HD) is rare incurable hereditary neurodegenerative disorder caused by CAG repeat expansion in the gene coding for the protein huntingtin (HTT). Mutated huntingtin (mHTT) undergoes fragmentation and accumulation, affecting cellular functions and leading to neuronal cell death. Porcine models of HD are used in preclinical testing of currently emerging disease modifying therapies. Such therapies are aimed at reducing mHTT expression, postpone the disease onset, slow down the progression, and point out the need of biomarkers to monitor disease development and therapy efficacy. Recently, extracellular vesicles (EVs), particularly exosomes, gained attention as possible carriers of disease biomarkers. We aimed to characterize HTT and mHTT forms/fragments in blood plasma derived EVs in transgenic (TgHD) and knock-in (KI-HD) porcine models, as well as in HD patients’ plasma. (2) Methods: Small EVs were isolated by ultracentrifugation and HTT forms were visualized by western blotting. (3) Results: The full length 360 kDa HTT co-isolated with EVs from both the pig model and HD patient plasma. In addition, a ~70 kDa mutant HTT fragment was specific for TgHD pigs. Elevated total huntingtin levels in EVs from plasma of HD groups compared to controls were observed in both pig models and HD patients, however only in TgHD were they significant (p = 0.02). (4) Conclusions: Our study represents a valuable initial step towards the characterization of EV content in the search for HD biomarkers.

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Section: Discussionmentioning

confidence: 99%

Huntingtin Co-Isolates with Small Extracellular Vesicles from Blood Plasma of TgHD and KI-HD Pig Models of Huntington’s Disease and Human Blood Plasma

Ananbeh

Novak

Juhás

et al. 2022

IJMS

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“…Expansion of polyglutamine (polyQ) repeats in specific proteins leads to neurodegenerative diseases such as Huntington's disease (HD) and spinocerebral ataxia (SCA1‐7) due to the proteotoxicity of these aggregation‐prone proteins (Bates et al, 2015 ; Chuang & Demontis, 2021 ; Labbadia & Morimoto, 2013 ). Proteolytic cleavage of huntingtin (Htt) is a key event in HD progression and truncated huntingtin fragments generally yield greater cellular toxicity than full‐length Htt.…”

Section: Polyglutamine Diseasesmentioning

confidence: 99%

Contribution of proteases to the hallmarks of aging and to age‐related neurodegeneration

et al. 2022

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Protein quality control ensures the degradation of damaged and misfolded proteins. Derangement of proteostasis is a primary cause of aging and age‐associated diseases. The ubiquitin–proteasome and autophagy‐lysosome play key roles in proteostasis but, in addition to these systems, the human genome encodes for ~600 proteases, also known as peptidases. Here, we examine the role of proteases in aging and age‐related neurodegeneration. Proteases are present across cell compartments, including the extracellular space, and their substrates encompass cellular constituents, proteins with signaling functions, and misfolded proteins. Proteolytic processing by proteases can lead to changes in the activity and localization of substrates or to their degradation. Proteases cooperate with the autophagy‐lysosome and ubiquitin–proteasome systems but also have independent proteolytic roles that impact all hallmarks of cellular aging. Specifically, proteases regulate mitochondrial function, DNA damage repair, cellular senescence, nutrient sensing, stem cell properties and regeneration, protein quality control and stress responses, and intercellular signaling. The capacity of proteases to regulate cellular functions translates into important roles in preserving tissue homeostasis during aging. Consequently, proteases influence the onset and progression of age‐related pathologies and are important determinants of health span. Specifically, we examine how certain proteases promote the progression of Alzheimer's, Huntington's, and/or Parkinson's disease whereas other proteases protect from neurodegeneration. Mechanistically, cleavage by proteases can lead to the degradation of a pathogenic protein and hence impede disease pathogenesis. Alternatively, proteases can generate substrate byproducts with increased toxicity, which promote disease progression. Altogether, these studies indicate the importance of proteases in aging and age‐related neurodegeneration.

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“…Several intracellular signaling pathways are involved in HD progression [ 20 ]. The possible effect of mHTT accumulation during the correct cellular function has been analyzed, mainly regarding neural systems.…”

Section: Kidneymentioning

confidence: 99%

“…Apart from the neuronal impairment of HD, some studies have described pathological phenotypes in the peripheral tissues of HD patients, including altered glucose homeostasis [ 8 ] and weight loss [ 9 ]. Other studies have analyzed the particular changes in blood cells such as erythrocytes [ 10 ] and lymphocytes [ 11 ], as well as in fibroblasts [ 12 ], immune blood cells [ 13 , 14 ], the pancreas [ 15 ], the heart [ 16 , 17 ], the retina [ 18 ], the liver [ 19 ], the kidney [ 20 ], pericytes and the blood–brain barrier [ 21 ] from HD patients. The models can aid understanding of how HTT affects peripheral tissues and contributes to disease progression.…”

Section: Introductionmentioning

confidence: 99%

A New Perspective on Huntington’s Disease: How a Neurological Disorder Influences the Peripheral Tissues

Gómez-Jaramillo

Cano-Cano

González-Montelongo

et al. 2022

IJMS

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Huntington’s disease (HD) is a neurodegenerative disorder caused by a toxic, aggregation-prone expansion of CAG repeats in the HTT gene with an age-dependent progression that leads to behavioral, cognitive and motor symptoms. Principally affecting the frontal cortex and the striatum, mHTT disrupts many cellular functions. In fact, increasing evidence shows that peripheral tissues are affected by neurodegenerative diseases. It establishes an active crosstalk between peripheral tissues and the brain in different neurodegenerative diseases. This review focuses on the current knowledge of peripheral tissue effects in HD animal and cell experimental models and identifies biomarkers and mechanisms involved or affected in the progression of the disease as new therapeutic or early diagnostic options. The particular changes in serum/plasma, blood cells such as lymphocytes, immune blood cells, the pancreas, the heart, the retina, the liver, the kidney and pericytes as a part of the blood–brain barrier are described. It is important to note that several changes in different mouse models of HD present differences between them and between the different ages analyzed. The understanding of the impact of peripheral organ inflammation in HD may open new avenues for the development of novel therapeutic targets.

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Systemic manifestation and contribution of peripheral tissues to Huntington’s disease pathogenesis

Cited by 37 publications

References 191 publications

Huntingtin Co-Isolates with Small Extracellular Vesicles from Blood Plasma of TgHD and KI-HD Pig Models of Huntington’s Disease and Human Blood Plasma

Huntingtin Co-Isolates with Small Extracellular Vesicles from Blood Plasma of TgHD and KI-HD Pig Models of Huntington’s Disease and Human Blood Plasma

Contribution of proteases to the hallmarks of aging and to age‐related neurodegeneration

A New Perspective on Huntington’s Disease: How a Neurological Disorder Influences the Peripheral Tissues

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