Beyond the brain: widespread pathology in Huntington's disease

Burg, Jorien M.M. van der; Björkqvist, Maria; Brundin, Patrik

doi:10.1016/s1474-4422(09)70178-4

Cited by 321 publications

(258 citation statements)

References 105 publications

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“…The best example of this hypothesis is Huntington disease, an autosomal dominant condition resulting from the expansion of the tri nucleotide CAG repeat ('polyQ repeat') in the hunting tin (HTT) gene. HF is among the leading causes of death in Huntington disease 114 , and the prevalence of HF in patients with Huntington disease is markedly increased com pared with age matched controls 115 [118][119][120] have demonstrated that whole body expression of polyQ proteins precipitates cardiomyopathy. Although this observation supports a direct involvement of the mutant huntingtin in development of cardiac disease, Huntington disease also features marked imbalance in the autonomic nervous system, leading to enhanced sympathetic tonus 121 , which might (partly) contribute to HF in Huntington disease.…”

Section: Derailment Owing To Genetic Mutationsmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

144

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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Section: Derailment Owing To Genetic Mutationsmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

144

126

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“…However, in addition to classical neurological symptoms, HD is complicated by peripheral pathology, including weight loss, altered body composition and skeletal muscle wasting [2], and both the mutant gene and protein are found in cells and tissues throughout the body [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Analysis of White Adipose Tissue Gene Expression Reveals CREB1 Pathway Altered in Huntington’s Disease

McCourt

Parker²,

Silajdžić

et al. 2015

JHD

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“…Additional clinical features of HD include peripheral organ dysfunction such as weight loss, skeletal muscle wasting, and metabolic and endocrine alterations (43). IPMK influences metabolism through its inhibition of AMP-activated kinase (AMPK) activation (44).…”

Section: Discussionmentioning

confidence: 99%

Huntington’s disease: Neural dysfunction linked to inositol polyphosphate multikinase

Ahmed

Sbodio

Harraz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Huntington's disease (HD) is a progressive neurodegenerative disease caused by a glutamine repeat expansion in mutant huntingtin (mHtt). Despite the known genetic cause of HD, the pathophysiology of this disease remains to be elucidated. Inositol polyphosphate multikinase (IPMK) is an enzyme that displays soluble inositol phosphate kinase activity, lipid kinase activity, and various noncatalytic interactions. We report a severe loss of IPMK in the striatum of HD patients and in several cellular and animal models of the disease. This depletion reflects mHtt-induced impairment of COUP-TF-interacting protein 2 (Ctip2), a striatal-enriched transcription factor for IPMK, as well as alterations in IPMK protein stability. IPMK overexpression reverses the metabolic activity deficit in a cell model of HD. IPMK depletion appears to mediate neural dysfunction, because intrastriatal delivery of IPMK abates the progression of motor abnormalities and rescues striatal pathology in transgenic murine models of HD.Huntington's disease | inositol polyphosphate multikinase | IPMK | Ctip2 | Akt

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Beyond the brain: widespread pathology in Huntington's disease

Cited by 321 publications

References 105 publications

Proteostasis in cardiac health and disease

Proteostasis in cardiac health and disease

Analysis of White Adipose Tissue Gene Expression Reveals CREB1 Pathway Altered in Huntington’s Disease

Huntington’s disease: Neural dysfunction linked to inositol polyphosphate multikinase

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