Huntington's Disease: Pathological Mechanisms and Therapeutic Strategies

Ramaswamy, Shilpa; Shannon, Kathleen M.; Kordower, Jeffrey H.

doi:10.3727/000000007783464687

Cited by 55 publications

(39 citation statements)

References 108 publications

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“…Misfolded HTT aggregation causes selective neuronal loss, primarily in the cortex and striatum, and also can lead to cognitive and motor impairments. The repetition of glutamine residue in HTT is critical for its toxicity: that is as the number of CAG repeats increases (CAG: gene code for glutamine), the HTT deposition and neurotoxicity are greater [79–81]. Interestingly, HSP70 is capable of preventing poly-glutamine-induced toxicity in HD models [82].…”

Section: Role Of Hsps In Different Neurodegenerative Diseasesmentioning

confidence: 99%

Molecular Chaperone Dysfunction in Neurodegenerative Diseases and Effects of Curcumin

Maiti

Manna

Veleri

et al. 2014

BioMed Research International

104

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The intra- and extracellular accumulation of misfolded and aggregated amyloid proteins is a common feature in several neurodegenerative diseases, which is thought to play a major role in disease severity and progression. The principal machineries maintaining proteostasis are the ubiquitin proteasomal and lysosomal autophagy systems, where heat shock proteins play a crucial role. Many protein aggregates are degraded by the lysosomes, depending on aggregate size, peptide sequence, and degree of misfolding, while others are selectively tagged for removal by heat shock proteins and degraded by either the proteasome or phagosomes. These systems are compromised in different neurodegenerative diseases. Therefore, developing novel targets and classes of therapeutic drugs, which can reduce aggregates and maintain proteostasis in the brains of neurodegenerative models, is vital. Natural products that can modulate heat shock proteins/proteosomal pathway are considered promising for treating neurodegenerative diseases. Here we discuss the current knowledge on the role of HSPs in protein misfolding diseases and knowledge gained from animal models of Alzheimer's disease, tauopathies, and Huntington's diseases. Further, we discuss the emerging treatment regimens for these diseases using natural products, like curcumin, which can augment expression or function of heat shock proteins in the cell.

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Section: Role Of Hsps In Different Neurodegenerative Diseasesmentioning

confidence: 99%

Molecular Chaperone Dysfunction in Neurodegenerative Diseases and Effects of Curcumin

Maiti

Manna

Veleri

et al. 2014

BioMed Research International

104

View full text Add to dashboard Cite

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“…Less than 1% of transplanted cells from autologous whole bone marrow transplanted into the striatum of an excitotoxic HD rat model expressed a neuronal marker [121]. However, functional recovery was seen in this study, and a survival advantage was observed in a separate study using human umbilical cord blood in a transgenic HD mouse model (reviewed in [122]). Further, in vitro proliferation of stem cells prior to transplantation, which should maximise their regenerative potential, may have a deleterious effect on graft survival if continued beyond four weeks (reviewed in [116]).…”

Section: Exogenous Cell Transplantmentioning

confidence: 73%

Established and Emerging Therapies for Huntingtons Disease

Wright¹,

Barker²

2007

CMM

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Huntington's disease is a genetic, neurodegenerative disorder causing cell dysfunction prior to cell death. Mechanisms that underlie the pathological changes continue to be elucidated, which in turn increases the number of potential therapeutic targets which have the ability to reverse or prevent further cell damage. As well as cell protection strategies, cell replacement techniques have been developed with the aim of replacing dead cells and restoring functional circuits. This review describes therapies used in clinical practice, therapies that have shown promise in experimental models either at the genetic or molecular level, and therapies that are subject to human clinical trials. It is likely that any successful therapy in clinical practice will involve a number of different approaches aimed at different targets in order to achieve both cell protection and cell replacement.

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“…HD is a good candidate for cell transplantation therapy have prompted studies to evaluate the potential of alternative renewable cell sources for transplantation therapy because there is no effective treatment and there is the potential for early intervention. for HD (29,39,40). In particular, human embryonic stem undertaken 1 week after 50 nM QA lesioning (at coordinates AP +0.5 mm, ML +2.7 mm, DV −5.0 mm).…”

Section: Introductionmentioning

confidence: 95%

Comparison of Transplant Efficiency between Spontaneously Derived and Noggin-Primed Human Embryonic Stem Cell Neural Precursors in the Quinolinic Acid Rat Model of Huntington's Disease

et al. 2010

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Human neural precursors (hNP) derived from embryonic stem cells (hESC) may provide a viable cellular source for transplantation therapy for Huntington's disease (HD). However, developing effective transplantation therapy for the central nervous system (CNS) using hESC relies on optimizing the in vitro production of hNP to control appropriate in vivo posttransplantation neuronal differentiation. The current study provides the first direct in vivo comparison of the transplant efficiency and posttransplantation characteristics of spontaneously derived and noggin-primed hNP following transplantation into the quinolinic acid (QA) rat model of HD. We show that spontaneously derived and noggin-primed hNP both survived robustly up to 8 weeks after transplantation into the QA-lesioned striatum of the adult rat. Transplanted hNP underwent extensive migration and large-scale differentiation towards a predominantly neuronal fate by 8 weeks posttransplantation. Furthermore, in vitro noggin priming of hNP specifically increased the extent of neuronal differentiation at both 4 and 8 weeks posttransplantation when compared to spontaneously derived hNP grafts. The results of this study suggest that in vitro noggin priming provides an effective mechanism by which to enhance hNP transplant efficiency for the treatment of HD.

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Huntington's Disease: Pathological Mechanisms and Therapeutic Strategies

Cited by 55 publications

References 108 publications

Molecular Chaperone Dysfunction in Neurodegenerative Diseases and Effects of Curcumin

Molecular Chaperone Dysfunction in Neurodegenerative Diseases and Effects of Curcumin

Established and Emerging Therapies for Huntingtons Disease

Comparison of Transplant Efficiency between Spontaneously Derived and Noggin-Primed Human Embryonic Stem Cell Neural Precursors in the Quinolinic Acid Rat Model of Huntington's Disease

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