Proteostasis in striatal cells and selective neurodegeneration in Huntingtonâ€™s disease

Margulis, Julia; Finkbeiner, Steven

doi:10.3389/fncel.2014.00218

Cited by 38 publications

(28 citation statements)

References 121 publications

(130 reference statements)

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“…Our observation is in agreement with previous observations which show that the expression of model ␤-sheet proteins leads to deficiency of the normal cytosolic stress response mediated by HSF1 and NF-B (33), and of an impaired heat shock response in mHtt expressing cells (38,40,76). Likewise, a deficiency in striatal neuron proteostasis machinery likely contributes to the select demise of these neurons in HD (77).…”

Section: Heat Shock For Mhtt Ib Formation and Tf De-repressionsupporting

confidence: 93%

Heat shock promotes inclusion body formation of mutant huntingtin (mHtt) and alleviates mHtt-induced transcription factor dysfunction

Chen¹,

Parekh²,

Seliman³

et al. 2018

Journal of Biological Chemistry

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PolyQ-expanded huntingtin (mHtt) variants form aggregates, termed inclusion bodies (IBs), in individuals with and models of Huntington's disease (HD). The role of IB diffusible mHtt in neurotoxicity remains unclear. Using a ponasterone (PA)-inducible cell model of HD, here we evaluated the effects of heat shock on the appearance and functional outcome of Htt103Q-EGFP expression. Quantitative image analysis indicated that 80-90% of this mHtt protein initially appears as "diffuse" signals in the cytosol, with IBs forming at high mHtt expression. A 2-h heat shock during the PA induction reduced the diffuse signal, but greatly increased mHtt IB formation in both cytosol and nucleus. Dose- and time-dependent mHtt expression suggested that nucleated polymerization drives IB formation. RNA-mediated knockdown of heat shock protein 70 (HSP70) and heat shock cognate 70 protein (HSC70) provided evidence for their involvement in promoting diffuse mHtt to form IBs. Reporter gene assays assessing the impacts of diffuse IB mHtt showed concordance of diffuse mHtt expression with the repression of heat shock factor 1, cAMP-responsive element-binding protein (CREB), and NF-κB activity. CREB repression was reversed by heat shock coinciding with mHtt IB formation. In an embryonic striatal neuron-derived HD model, the chemical chaperone sorbitol similarly promoted the structuring of diffuse mHtt into IBs and supported cell survival under stress. Our results provide evidence that mHtt IB formation is a chaperone-supported cellular coping mechanism that depletes diffusible mHtt conformers, alleviates transcription factor dysfunction, and promotes neuron survival.

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Section: Heat Shock For Mhtt Ib Formation and Tf De-repressionsupporting

confidence: 93%

Heat shock promotes inclusion body formation of mutant huntingtin (mHtt) and alleviates mHtt-induced transcription factor dysfunction

Chen¹,

Parekh²,

Seliman³

et al. 2018

Journal of Biological Chemistry

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“…Exactly how the UPS is affected is debated, some suggesting that the proteasome is sequestered in mHTT inclusion bodies and inhibited by entrapment, but other studies indicating that the sequestration is only transient and therefore does not inhibit the UPS . Recent studies have suggested that the UPS in striatal medium spiny neurons has lower activity and is more vulnerable to UPS stressors than cortical and cerebellar cells, thus providing an explanation as to why striatal medium spiny neurons are selectively lost in the early phases of pathology . Our results confirm the involvement of the UPS in HD.…”

Section: Discussionsupporting

confidence: 80%

Ubiquitin: a potential cerebrospinal fluid progression marker in Huntington's disease

Vinther-Jensen

Simonsen

Budtz‐Jørgensen

et al. 2015

Euro J of Neurology

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Multiple studies have shown that the ubiquitin-proteasome system is involved in Huntington's disease pathogenesis and understanding of this involvement may have therapeutic potential in humans. This is the first study on cerebrospinal fluid to confirm the involvement of the ubiquitin-proteasome system in Huntington's disease. Furthermore it is shown that ubiquitin increases with disease progression and CAG-age product score and therefore may have the potential as a Huntington's disease progression marker, also prior to motor onset.

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“…41 Their many functional roles are underscored by changes they may undergo as a result of post-translational modification, 42 the potential for their trans-cellular activities 43 and the role they play in a wide variety diseases including but not limited to Pompe disease, Huntington disease, cancer, pulmonary and cardiovascular disease. 6,[44][45][46][47][48][49][50][51] Not surprisingly, considering their role in these processes, targeting the chaperones has become a legitimate therapeutic avenue. 49,52 The HSR is the most evolutionarily ancient of the PQC pathways, enlisting molecular chaperones ( Figure 1, top panel), such as the HSPs, to manage two primary functions within the cell: transiently interact with nascent unfolded polypeptides to guide them towards their proper folded conformation and target terminally misfolded proteins for degradation.…”

Section: The Heat Shock Responsementioning

confidence: 99%

Proteotoxicity and Cardiac Dysfunction

2013

N Engl J Med

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Baseline physiological function of the mammalian heart is under the constant threat of environmental or intrinsic pathological insults. Cardiomyocyte proteins are thus subject to unremitting pressure to function optimally and this depends upon them assuming and maintaining proper conformation. This review explores the multiple defenses a cell may employ for its proteins to assume and maintain correct protein folding and conformation. There are multiple quality control mechanisms to ensure that nascent polypeptides are properly folded and mature proteins maintain their functional conformation. When proteins do misfold, either in the face of normal or pathologic stimuli or because of intrinsic mutations or post-translational modifications, they must either be refolded correctly or recycled. In the absence of these corrective processes, they may become toxic to the cell. Herein, we explore some of the underlying mechanisms that lead to proteotoxicity. The continued presence and chronic accumulation of misfolded or unfolded proteins can be disastrous in cardiomyocytes as these misfolded proteins can lead to aggregation or the formation of soluble peptides that are proteotoxic. This in turn leads to compromised protein quality control and precipitating a downward spiral of the cell's ability to maintain protein homeostasis. Some underlying mechanisms are discussed and the therapeutic potential of interfering with proteotoxicity in the heart is explored.

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Proteostasis in striatal cells and selective neurodegeneration in Huntingtonâ€™s disease

Cited by 38 publications

References 121 publications

Heat shock promotes inclusion body formation of mutant huntingtin (mHtt) and alleviates mHtt-induced transcription factor dysfunction

Heat shock promotes inclusion body formation of mutant huntingtin (mHtt) and alleviates mHtt-induced transcription factor dysfunction

Ubiquitin: a potential cerebrospinal fluid progression marker in Huntington's disease

Proteotoxicity and Cardiac Dysfunction

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