Functional alterations of the ubiquitin-proteasome system in motor neurons of a mouse model of familial amyotrophic lateral sclerosis†

Cheroni, Cristina; Marino, Marianna; Tortarolo, Massimo; Veglianese, Pietro; Biasi, S. De; Fontana, Elena; Zuccarello, Laura Vitellaro; Maynard, Christa J.; Dantuma, Nico P.; Bendotti, Caterina

doi:10.1093/hmg/ddn319

Cited by 142 publications

(124 citation statements)

References 52 publications

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“…The same reporter mice that were applied in our study have confirmed UPS dysfunction in prion-infected mice (42) and in transgenic mice overexpressing a mutant SOD1 responsible for familial amyotrophic lateral sclerosis (43) showing that these mice are suited for in vivo assessment of the UPS. In contrast, in three polyQ disease models, namely SCA7 (10), spinal and bulbar muscular atrophy (11) and mice expressing N-mutHtt, the UPS remains operative.…”

Section: Discussionsupporting

confidence: 61%

Accumulation of ubiquitin conjugates in a polyglutamine disease model occurs without global ubiquitin/proteasome system impairment

Maynard

Böttcher

Ortega

et al. 2009

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

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Aggregation-prone proteins have been suggested to overwhelm and impair the ubiquitin/proteasome system (UPS) in polyglutamine (polyQ) disorders, such as Huntington's disease (HD). Overexpression of an N-terminal fragment of mutant huntingtin (NmutHtt), an aggregation-prone polyQ protein responsible for HD, obstructs the UPS in cellular models. Furthermore, based on the accumulation of polyubiquitin conjugates in brains of R6/2 mice, which express human N-mutHtt and are one of the most severe polyQ disorder models, it has been proposed that UPS dysfunction is a consistent feature of this pathology, occurring in both in vitro and in vivo models. Here, we have exploited transgenic mice that ubiquitously express a ubiquitin fusion degradation proteasome substrate to directly assess the functionality of the UPS in R6/2 mice or the slower onset R6/1 mice. Although expression of N-mutHtt caused a general inhibition of the UPS in PC12 cells, we did not observe an increase in the levels of proteasome reporter substrate in the brains of R6/2 and R6/1 mice. We show that the increase in ubiquitin conjugates in R6/2 mice can be primarily attributed to an accumulation of large ubiquitin conjugates that are different from the conjugates observed upon UPS inhibition. Together our data show that polyubiquitylated proteins accumulate in R6/2 brain despite a largely operative UPS, and suggest that neurons are able to avoid or compensate for the inhibitory effects of N-mutHtt.Huntington ͉ neurodegeneration ͉ protein degradation T he primary proteolytic machinery responsible for the turnover of proteins in the cytosol and nuclei of cells, including the destruction of misfolded or otherwise abnormal proteins, is the ubiquitin/proteasome system (UPS) (1). The UPS is in essence a two-step process: the targeting of proteins through the covalent linkage of polyubiquitin chains (2), and the destruction of ubiquitylated proteins by the proteasome (3). A number of studies have implicated UPS dysfunction in a range of polyglutamine (polyQ) neurodegenerative diseases (4). The aggregation-prone polyQ proteins are postulated to impair the UPS in these diseases, either by overloading the capacity of the cell's UPS machinery (5), by sequestration of essential components of the UPS into inclusions (6), or by obstruction of the proteasome (7). If polyQ proteins themselves inhibit the system crucial to their own degradation, this could elicit a self-perpetuating pathogenic cascade of events, both accelerating the accumulation of the toxic protein, and impairing essential regulatory functions of the UPS (4). With the help of specifically designed reporter substrates, it has been shown that polyQ proteins can cause UPS impairment in cell lines (5,8,9). However, since these experiments rely on acute overexpression of the polyQ protein in cells with limited physiological relevance, it is difficult to extrapolate these findings to the status of the UPS during the progression of the disease in patients.In contrast to the observation with in vitro models, ...

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Section: Discussionsupporting

confidence: 61%

Accumulation of ubiquitin conjugates in a polyglutamine disease model occurs without global ubiquitin/proteasome system impairment

Maynard

Böttcher

Ortega

et al. 2009

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

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“…Loss of functional CFTR has been associated with intracellular aggregate formation, accumulation of polyubiquitinated proteins and aberrant autophagy in lung epithelial cells [79]. It needs to be further investigated whether proteasome function is also impaired in CFTR-aberrant cells, as was shown for mutant surfactant protein C and aggregated neuronal proteins [80][81][82][83]. Such a scenario is very reminiscent of protein quality diseases of the brain and heart, where reduced proteasome activity exaggerates cellular stress and contributes to a vicious cycle of cellular dysfunction [3,4].…”

Section: Cystic Fibrosismentioning

confidence: 99%

What shall we do with the damaged proteins in lung disease? Ask the proteasome!

Meiners

Eickelberg

2012

Eur Respir J

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The proteasome constitutes the main protein waste disposal and recycling system of the cell. Together with endoplasmic reticulum stress and the autophagosome pathway, it takes centre stage in cellular protein quality control.In lung research, the proteasome is, first of all, a promising therapeutic target to intervene in the malignant growth of lung cancer cells. Therapeutic targeting of the proteasome has also been extended to pulmonary fibrosis and asthma using animal models. Moreover, the proteasome is involved in lung pathogenesis. In cystic fibrosis, rapid proteasomal degradation of mutant cystic fibrosis transmembrane conductance regulator contributes to loss of function of lung epithelial cells. In chronic obstructive pulmonary disease (COPD), pulmonary proteasome expression and activity are downregulated and inversely correlate with lung function. In addition, as the proteasome degrades signalling mediators that have been oxidatively modified in COPD, it contributes to further compromise cellular function.The consequences of proteasomal dysfunction are loss of protein quality control, accumulation of misfolded proteins and exacerbation of cellular stress, which are also hallmarks of protein quality diseases and premature ageing. This suggests that proteasome dysfunction can be regarded as a new pathomechanism for chronic lung diseases, awaiting further therapeutic exploration in the future.

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“…Our data provide unique in vivo evidence that proteasomal insufficiency is ubiquitously encountered in various forms of inherited retinal degeneration associated with misfolding or mistargeting of both cytosolic and membrane proteins. Whereas the studies of other neurodegenerative diseases revealed a strong association between the underlying pathology and impaired proteasomal function (37)(38)(39)(40), this important stress factor largely escaped the attention of researchers studying retinitis pigmentosa and allied diseases. Given that inherited retinal disorders are typically diagnosed at their early stages, the emerging therapeutic strategies targeting proteasomes in neurodegeneration (41) could be particularly efficacious in treating these blinding conditions.…”

Section: Gβmentioning

confidence: 99%

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

Lobanova

Finkelstein

Skiba

et al. 2013

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

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Inherited retinal degenerations, caused by mutations in over 100 individual genes, affect approximately 2 million people worldwide. Many of the underlying mutations cause protein misfolding or mistargeting in affected photoreceptors. This places an increased burden on the protein folding and degradation machinery, which may trigger cell death. We analyzed how these cellular functions are affected in degenerating rods of the transducin γ-subunit (Gγ 1 ) knockout mouse. These rods produce large amounts of transducin β-subunit (Gβ 1 ), which cannot fold without Gγ 1 and undergoes intracellular proteolysis instead of forming a transducin βγ-subunit complex. Our data revealed that the most critical pathobiological factor leading to photoreceptor cell death in these animals is insufficient capacity of proteasomes to process abnormally large amounts of misfolded protein. A decrease in the Gβ 1 production in Gγ 1 knockout rods resulted in a significant reduction in proteasomal overload and caused a striking reversal of photoreceptor degeneration. We further demonstrated that a similar proteasomal overload takes place in photoreceptors of other mutant mice where retinal degeneration has been ascribed to protein mistargeting or misfolding, but not in mice whose photoreceptor degenerate as a result of abnormal phototransduction. These results establish the prominence of proteasomal insufficiency across multiple degenerative diseases of the retina, thereby positioning proteasomes as a promising therapeutic target for treating these debilitating conditions. neurodegenerative diseases | protein degradation

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Functional alterations of the ubiquitin-proteasome system in motor neurons of a mouse model of familial amyotrophic lateral sclerosis†

Cited by 142 publications

References 52 publications

Accumulation of ubiquitin conjugates in a polyglutamine disease model occurs without global ubiquitin/proteasome system impairment

Accumulation of ubiquitin conjugates in a polyglutamine disease model occurs without global ubiquitin/proteasome system impairment

What shall we do with the damaged proteins in lung disease? Ask the proteasome!

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

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