Proteostasis and Movement Disorders: Parkinson's Disease and Amyotrophic Lateral Sclerosis

Bosco, Daryl A.; LaVoie, Matthew J.; Petsko, Gregory A.; Ringe, Dagmar

doi:10.1101/cshperspect.a007500

Cited by 60 publications

(56 citation statements)

References 161 publications

(195 reference statements)

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“…The identification of a Bax E3 ligase expands the established pathways for regulating Bax function to include ubiquitination as a means of promoting cell survival and may also reconcile prior findings of the de-ubiquitinating enzyme Ku70 potentiating Baxdependent cell death (24). Furthermore, these findings provide insight into the neuronal consequences of parkin deficiency as they relate to inherited defects in the Parkin gene or the numerous stress conditions and posttranslational modifications that disrupt normal parkin function [reviewed elsewhere (25)]. Here we demonstrate the parkin-dependent ubiquitination of endogenous Bax using parkin stable and transiently transfected dopaminergic MES cells and numerous MEF lines.…”

Section: Discussionmentioning

confidence: 80%

“…Based on the unique vulnerability of the substantia nigra and locus coeruleus in Parkin-null patients, however, we speculate that parkin plays a specialized role in modulating Bax within these discrete neuronal subpopulations. The interaction between parkin and Bax may also play a role in the natural age-dependent degeneration of catecholaminergic neurons in the normal human brain (33)(34)(35), which may be a consequence of the age-dependent changes in parkin solubility (36) or stress-induced loss of parkin function [reviewed elsewhere (25)]. …”

Section: Discussionmentioning

confidence: 99%

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The ubiquitin E3 ligase parkin regulates the proapoptotic function of Bax

Johnson

Berger²,

Cortese³

et al. 2012

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

156

144

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Autosomal recessive loss-of-function mutations within the PARK2 gene functionally inactivate the E3 ubiquitin ligase parkin, resulting in neurodegeneration of catecholaminergic neurons and a familial form of Parkinson disease. Current evidence suggests both a mitochondrial function for parkin and a neuroprotective role, which may in fact be interrelated. The antiapoptotic effects of parkin have been widely reported, and may involve fundamental changes in the threshold for apoptotic cytochrome c release, but the substrate(s) involved in parkin dependent protection had not been identified. Here, we demonstrate the parkin-dependent ubiquitination of endogenous Bax comparing primary cultured neurons from WT and parkin KO mice and using multiple parkin-overexpressing cell culture systems. The direct ubiquitination of purified Bax was also observed in vitro following incubation with recombinant parkin. We found that parkin prevented basal and apoptotic stressinduced translocation of Bax to the mitochondria. Moreover, an engineered ubiquitination-resistant form of Bax retained its apoptotic function, but Bax KO cells complemented with lysine-mutant Bax did not manifest the antiapoptotic effects of parkin that were observed in cells expressing WT Bax. These data suggest that Bax is the primary substrate responsible for the antiapoptotic effects of parkin, and provide mechanistic insight into at least a subset of the mitochondrial effects of parkin.Parkinson's disease | apoptosis | neuroprotection | mitophagy P arkinson disease (PD) is a neurodegenerative disorder that affects 1-3% of the population over the age of 65 years (1). The symptoms include tremor, rigidity, bradykinesia, and postural instability. These physical characteristics are caused by the progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta and, to a lesser extent, the catecholaminergic neurons of the locus coeruleus. Although most cases of PD are sporadic in nature, a small number of genes are responsible for the rare familial forms of PD (2). Loss-of-function mutations within the PARK2 locus, which encodes the protein parkin, are the most common cause of autosomal recessive PD (3).Parkin is a 465-amino acid protein that is expressed in multiple tissues and functions as an E3 ubiquitin ligase (4). Ubiquitination of substrates is a tightly regulated process, requiring the combined activity of three enzymes: an E1 ubiquitin-activating enzyme, an E2 ubiquitin conjugating enzyme, and an E3 ubiquitin ligase (5). E3 ubiquitin ligases are responsible for substrate recognition, and as such contribute the specificity of a ubiquitin reaction. Defects in parkin-mediated ubiquitination may result in the failure to target specific substrates for degradation, leading to accumulation of potentially toxic proteins and consequent cell death (6). Parkin is widely neuroprotective (7); however, many of the putative parkin substrates reported to date are not thought to directly mediate toxicity in such a simple fashion [reviewed elsewhere (8...

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

The ubiquitin E3 ligase parkin regulates the proapoptotic function of Bax

Johnson

Berger²,

Cortese³

et al. 2012

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

156

144

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“…Proteasome and autophagy dysfunction in age-related diseases Gain-of-toxic-function diseases, such as AD, HD, PD and amyotrophic lateral sclerosis (ALS), in which aggregationmediated proteotoxicity exceeds the cellular clearance machinery, are more frequent late in life even though different toxic proteins are involved in their onset [2][3][4]10,14,15 . The pathophysiological significance of protein aggregates is vaguely known.…”

Section: Loss Of Clearance Mechanisms As a Determinant Of Ageingmentioning

confidence: 99%

“…ALS is another progressive neurodegenerative movement disorder but affects motor neurons 3 . Impairment of the proteasome in these neurons by conditional knockout of Psmc4/Rpt3 revealed loss of motor neurons, locomotor dysfunction and accumulation of aggregates of TDP-43 and FUS proteins, features typical of ALS 113 .…”

Section: Loss Of Clearance Mechanisms As a Determinant Of Ageingmentioning

confidence: 99%

The role of protein clearance mechanisms in organismal ageing and age-related diseases

2014

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“…The disease phenotype is characterized by the formation of intracellular or extracellular plaques or inclusions containing amyloid forms of the diseasecausing proteins. Despite this commonality, most neurodegenerative disease-related proteins, whose biochemical features have been extensively analyzed in systems in vivo and in vitro, do not share primary sequence features, or functional characteristics, but do aggregate into amyloid superstructures in a generally similar fashion (4,(7)(8)(9). Given the pronounced association of amyloid formation with disease, a long-standing hypothesis assumed that amyloid inclusions were the culprits of pathology.…”

mentioning

confidence: 99%

Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity

Weisberg

Lyakhovetsky

Werdiger

et al. 2012

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

126

144

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Neurodegenerative diseases constitute a class of illnesses marked by pathological protein aggregation in the brains of affected individuals. Although these disorders are invariably characterized by the degeneration of highly specific subpopulations of neurons, protein aggregation occurs in all cells, which indicates that toxicity arises only in particular cell biological contexts. Aggregation-associated disorders are unified by a common cell biological feature: the deposition of the culprit proteins in inclusion bodies. The precise function of these inclusions remains unclear. The starting point for uncovering the origins of disease pathology must therefore be a thorough understanding of the general cell biological function of inclusions and their potential role in modulating the consequences of aggregation. Here, we show that in human cells certain aggregate inclusions are active compartments. We find that toxic aggregates localize to one of these compartments, the juxtanuclear quality control compartment (JUNQ), and interfere with its quality control function. The accumulation of SOD1G93A aggregates sequesters Hsp70, preventing the delivery of misfolded proteins to the proteasome. Preventing the accumulation of SOD1G93A in the JUNQ by enhancing its sequestration in an insoluble inclusion reduces the harmful effects of aggregation on cell viability. aggregation quality control | ALS | insoluble protein deposit | protein folding

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Proteostasis and Movement Disorders: Parkinson's Disease and Amyotrophic Lateral Sclerosis

Cited by 60 publications

References 161 publications

The ubiquitin E3 ligase parkin regulates the proapoptotic function of Bax

The ubiquitin E3 ligase parkin regulates the proapoptotic function of Bax

The role of protein clearance mechanisms in organismal ageing and age-related diseases

Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity

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