Origin of the Mutations in the parkin Gene in Europe: Exon Rearrangements Are Independent Recurrent Events, whereas Point Mutations May Result from Founder Effects

Periquet, Magali; Lücking, Christoph B.; Vaughan, Jenny; Bonifati, Vincenzo; Dürr, Alexandra; Michele, Giuseppe De; Horstink, M.W.I.M.; Farrer, Matthew J.; Иллариошкин, С. Н.; Pollak, Pierre; Borg, M.; Brefel‐Courbon, Christine; Denèfle, Patrice; Meco, Giuseppe; Gasser, Thomas; Breteler, Monique M.B.; Wood, Nicholas W.; Agid, Yves; Brice, Alexis

doi:10.1086/318791

Cited by 105 publications

(83 citation statements)

References 31 publications

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“…Exon 2 of parkin was deleted because it encodes most of the functionally important ubiquitinlike domain (14-16), mutations in exon 2 have been reported in patients with [17][18][19], and RNA splicing from exons 1 to 3, if successful, is predicted to change the reading frame and produce a 4-aa peptide (Met-Ile-Glu-Leu). Deletion of exon 2 was confirmed at the parkin genomic locus with Southern analysis and PCR ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Parkin-deficient mice are not a robust model of parkinsonism

Perez

Palmiter

2005

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

418

338

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Mutations in the human parkin gene cause autosomal recessive juvenile parkinsonism, a heritable form of Parkinson's disease (PD). To determine whether mutations in the mouse parkin gene (Park2) also result in a parkinsonian phenotype, we generated mice with a targeted deletion of parkin exon 2. Using an extensive behavioral screen, we evaluated neurological function, motor ability, emotionality, learning, and memory in aged Parkin-deficient mice. The behavioral profile of Parkin-deficient mice on a B6;129S4 genetic background was strikingly similar to that of control mice, and most differences were not reproducible by using coisogenic mice on a 129S4 genetic background. Moreover, catecholamine levels in the striatum, olfactory bulb, and spinal cord of Parkin-deficient mice were normal. In contrast to previous studies using independently generated Parkin-deficient mice, we found no evidence for nigrostriatal, cognitive, or noradrenergic dysfunction. Understanding why Parkin-deficient mice do not exhibit robust signs of parkinsonism could advance knowledge and treatment of PD.mouse behavior ͉ dopamine ͉ norepinephrine ͉ gene knockout ͉ Parkinson P arkinson's disease (PD) is a devastating neurodegenerative disorder that affects Ͼ500,000 people in the United States alone (1). The age-related and progressive signs of PD classically include resting tremor, muscular rigidity, abnormal gait, and slow movement; however, other signs and symptoms associated with parkinsonism can include somatosensory deficits, impaired cognitive function, and psychiatric disturbances (2-4). Many PD signs result from the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Dopamine replacement medications often succeed in managing parkinsonism; however, these treatments lose effectiveness, have undesirable effects, and do not prevent the underlying neurodegeneration. Understanding the molecular mechanism of dopaminergic neuron degeneration would facilitate the development of therapies that prevent PD.The identification of mutations in single genes that result in familial parkinsonism will help advance our understanding of the molecular mechanism of PD. Mutations in the human parkin gene are responsible for autosomal recessive juvenile parkinsonism (AR-JP), a heritable disease that resembles PD (5). The Parkin protein is a widely expressed, E3 ubiquitin-protein ligase that is thought to target specific proteins for proteasomal degradation (5-7). Presumably, in the absence of Parkin function, these protein targets accumulate to toxic levels and cause dopamine neuron degeneration.To investigate how mutations in parkin lead to parkinsonism, we generated mice with a targeted disruption of Park2. We hypothesized that Parkin-deficient mice would recapitulate the behavioral signs and pathology of AR-JP. During our investigation, several other groups independently generated and described mice with various targeted deletions of the parkin gene (8-11); however, results from these studies have raised many new issues. First, the b...

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Section: Resultsmentioning

confidence: 99%

Parkin-deficient mice are not a robust model of parkinsonism

Perez

Palmiter

2005

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

418

338

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“…5D). Such Parkin cleavage is predicted to be inactivating based on structure-function analyses and correlations of mutations in this region of the Parkin gene with early onset autosomal recessive parkinsonism (25,26).…”

Section: Inflammasomes Mediate Parkin Cleavage and Inhibit Mitophagymentioning

confidence: 99%

Inflammasome activation leads to Caspase-1–dependent mitochondrial damage and block of mitophagy

Nagasu

Murakami

et al. 2014

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

381

320

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Inflammasomes are intracellular sensors that couple detection of pathogens and cellular stress to activation of Caspase-1, and consequent IL-1β and IL-18 maturation and pyroptotic cell death. Here, we show that the absent in melanoma 2 (AIM2) and nucleotidebinding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasomes trigger Caspase-1-dependent mitochondrial damage. Caspase-1 activates multiple pathways to precipitate mitochondrial disassembly, resulting in mitochondrial reactive oxygen species (ROS) production, dissipation of mitochondrial membrane potential, mitochondrial permeabilization, and fragmentation of the mitochondrial network. Moreover, Caspase-1 inhibits mitophagy to amplify mitochondrial damage, mediated in part by cleavage of the key mitophagy regulator Parkin. In the absence of Parkin activity, increased mitochondrial damage augments pyroptosis, as indicated by enhanced plasma membrane permeabilization and release of danger-associated molecular patterns (DAMPs). Therefore, like other initiator caspases, Caspase-1 activation by inflammasomes results in mitochondrial damage.inflammasomes | mitochondrial damage | pyroptosis | mitophagy

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“…Spontaneous Misfolding of a Parkin Mutant Linked to AR-JP-Pathogenic parkin mutations linked to AR-JP are distributed throughout the parkin gene and include missense, nonsense, and frameshift mutations as well as exon deletions and multiplications (1,(17)(18)(19)(20)(21). Some of the parkin mutants have been shown to interfere with the ubiquitin-protein isopeptide ligase activity of parkin due to impaired protein interactions.…”

Section: Thermal and Oxidative Stress Induces Misfolding Of Wild-mentioning

confidence: 99%

“…Misfolding-A wide variety of parkin mutants have been described worldwide, including exon deletions, duplications and triplications, missense, nonsense, and frameshift mutations (1,(17)(18)(19)(20)(21). A cluster of mutations localizes to the C-terminal RING box; consistently, the majority of mutants characterized so far impairs the interaction of parkin with ubiquitin carrier proteins or with its substrates.…”

Section: Inactivation Of a Pathogenic Parkin Mutant By Spontaneousmentioning

confidence: 99%

Inactivation of Parkin by Oxidative Stress and C-terminal Truncations

Winklhofer

Henn

Kay-Jackson

et al. 2003

Journal of Biological Chemistry

125

111

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Loss of parkin function is linked to autosomal recessive juvenile parkinsonism. Here we show that proteotoxic stress and short C-terminal truncations induce misfolding of parkin. As a consequence, wild-type parkin was depleted from a high molecular weight complex and inactivated by aggregation. Similarly, the pathogenic parkin mutant W453Stop, characterized by a Cterminal deletion of 13 amino acids, spontaneously adopted a misfolded conformation. Mutational analysis indicated that C-terminal truncations exceeding 3 amino acids abolished formation of detergent-soluble parkin. In the cytosol scattered aggregates of misfolded parkin contained the molecular chaperone Hsp70. Moreover, increased expression of chaperones prevented aggregation of wild-type parkin and promoted folding of the W453Stop mutant. Analyzing parkin folding in vitro indicated that parkin is aggregation-prone and that its folding is dependent on chaperones. Our study demonstrates that C-terminal truncations impede parkin folding and reveal a new mechanism for inactivation of parkin.Autosomal recessive juvenile parkinsonism (AR-JP), 1 the major cause of early onset parkinsonism, is characterized by mutations within the parkin gene. Parkin, a 465-amino acid protein, shows homology to ubiquitin at the N terminus and harbors a RING box near the C terminus, consisting of two RING finger motifs that flank a cysteine-rich domain (in-between RING fingers domain) (1, 2). Functional studies established that parkin acts as a ubiquitin-protein isopeptide ligase and that pathogenic mutations compromise this activity (3-6). As a consequence, substrates destined for proteasomal degradation via parkin might accumulate in parkin-deficient cells. Indeed, recent studies with cell culture models provide experimental evidence for such a scenario. It was shown that disease-related mutations in the parkin gene impair protein interactions of parkin with either a parkin substrate or another component of the ubiquitin ligase complex. Accumulation of Pael-R, one of the identified parkin substrates, causes endoplasmic reticulum (ER) stress, indicating that parkin has the potential to suppress unfolded protein stress-induced cell death (3, 4). Recent studies (7) revealed that parkin deficiency potentiates the accumulation of cyclin E and promotes apoptosis in neuronal cells exposed to excitotoxic stress. Interestingly, parkin is a significant component of Lewy bodies, the histopathologic hallmark of PD (5,8,9). Furthermore, it has been shown that parkin is protective against the toxic effects of proteasomal dysfunction and mutant ␣-synuclein (10), implying that the impact of parkin function and dysfunction might not be restricted to the entity of AR-JP.It still remains enigmatic why dopaminergic neurons in the substantia nigra are highly vulnerable in AR-JP, as parkin as well as its substrates identified so far are not selectively expressed in these cells. However, an inherent feature of dopaminergic neurons is an elevated level of reactive oxygen and nitrogen species due to...

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Origin of the Mutations in the parkin Gene in Europe: Exon Rearrangements Are Independent Recurrent Events, whereas Point Mutations May Result from Founder Effects

Cited by 105 publications

References 31 publications

Parkin-deficient mice are not a robust model of parkinsonism

Parkin-deficient mice are not a robust model of parkinsonism

Inflammasome activation leads to Caspase-1–dependent mitochondrial damage and block of mitophagy

Inactivation of Parkin by Oxidative Stress and C-terminal Truncations

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