Hallervorden-Spatz Syndrome

Dooling, Elizabeth C.; Schoene, William C.; Richardson, Edward P.

doi:10.1001/archneur.1974.00490310072012

Cited by 244 publications

(138 citation statements)

References 35 publications

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“…Thus, the oxidative cross-linking of ␣-synuclein may act at different steps in the formation of large intracellular lesions. This model is consistent with the elevated oxidative environment of dopaminergic neurons, which are the neurons that are primarily affected in PD (25), with the presence of oxidized metabolites in dementia with LBs (47) 2 as well as the neurons that are burdened with iron deposition in Hallervoden-Spatz disease (48). On the other hand, oxidative stress has not been demonstrated to occur in multiple system atrophy; however, the observation that GCIs contain nitrated proteins 2 suggests that oxidative stress and ␣-synuclein aggregation are common pathological features in these neurodegenerative diseases and synucleinopathies.…”

Section: Figsupporting

confidence: 74%

Dityrosine Cross-linking Promotes Formation of Stable α-Synuclein Polymers

Souza¹,

Giasson²,

Chen³

et al. 2000

Journal of Biological Chemistry

536

225

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Intracellular proteinaceous aggregates are hallmarks of many common neurodegenerative disorders, and recent studies have shown that ␣-synuclein is a major component of several pathological intracellular inclusions, including Lewy bodies in Parkinson's disease (PD) and glial cell inclusions in multiple system atrophy. However, the molecular mechanisms underlying ␣-synuclein aggregation into filamentous inclusions remain unknown. Since oxidative and nitrative stresses are potential pathogenic mediators of PD and other neurodegenerative diseases, we asked if oxidative and/or nitrative events alter ␣-synuclein and induce it to aggregate. Here we show that exposure of human recombinant ␣-synuclein to nitrating agents (peroxynitrite/CO 2 or myeloperoxidase/H 2 O 2 /nitrite) induces formation of nitrated ␣-synuclein oligomers that are highly stabilized due to covalent cross-linking via the oxidation of tyrosine to form o,o-dityrosine. We also demonstrate that oxidation and nitration of pre-assembled ␣-synuclein filaments stabilize these filaments to withstand denaturing conditions and enhance formation of SDS-insoluble, heat-stable high molecular mass aggregates. Thus, these data suggest that oxidative and nitrative stresses are involved in mechanisms underlying the pathogenesis of Lewy bodies and glial cell inclusions in PD and multiple system atrophy, respectively, as well as ␣-synuclein pathologies in other synucleinopathies.Accumulations of proteinaceous fibrils are a common neuropathological feature of several different sporadic and hereditary neurodegenerative diseases (1, 2). The neuronal presynaptic protein ␣-synuclein is a conspicuous component of intraneuronal inclusions of Lewy bodies (LBs) 1 and Lewy neurites (3-11), two prominent pathological features of Parkinson's disease (PD). Mutations in ␣-synuclein have been linked to familial , and these mutations appear to cause biophysical changes in these proteins that accelerate their fibrillogenesis in vitro (15-18). However, LBs and Lewy neurites in sporadic PD and dementia with LBs (3-11) as well as glial cytoplasmic inclusions (GCIs) in multiple system atrophy (19 -23) contain filaments formed by wild-type ␣-synuclein. Moreover, high molecular mass aggregates of wild-type ␣-synuclein that are resistant to strong denaturing conditions have been recovered from purified LBs and GCIs, (4, 22-24), suggesting that covalently modified ␣-synuclein may be predisposed to form these inclusions. However, the precise molecular alterations of wild-type ␣-synuclein that lead to the formation of aggregates in these diseases are unknown.Oxidative stress has been implicated in pathogenic mechanisms of PD and many other neurodegenerative diseases (25)(26)(27). Both analytical and immunological methodologies have revealed the presence of oxidized and nitrated proteins in a number of neurodegenerative disorders (27-32), supporting a role for oxidants and nitrating agents in the development of these diseases. Moreover, ␣-synuclein inclusions in brains from patients with PD (28), ...

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Section: Figsupporting

confidence: 74%

Dityrosine Cross-linking Promotes Formation of Stable α-Synuclein Polymers

Souza¹,

Giasson²,

Chen³

et al. 2000

Journal of Biological Chemistry

536

225

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“…Pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome, OMIM #234200 and #606157) is an autosomal recessively inherited, neurodegenerative disease typically characterized by childhood onset of disturbance in gait, dystonia, dysarthria and dysphagia (Dooling et al 1974). A primary site of degeneration is the globus pallidus, in which cellular tissue is gradually replaced by iron, culminating in a characteristic image referred to as 'eye of the tiger' on T2-weighted magnetic resonance imaging.…”

Section: Introductionmentioning

confidence: 99%

Deprivation of pantothenic acid elicits a movement disorder and azoospermia in a mouse model of pantothenate kinase‐associated neurodegeneration

Kuo

Hayflick

Gitschier

2007

J of Inher Metab Disea

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SummaryWe asked whether a movement disorder could be elicited by deprivation of pantothenic acid (PA; vitamin B 5 ), the substrate for the enzyme pantothenate kinase 2 (PANK2), which is deficient in the inherited neurological disorder PKAN (pantothenate kinase-associated neurodegeneration formerly called Hallervorden-Spatz syndrome). This study was undertaken because mice made null for Pank2 failed to show the neurological manifestations of the human disease. Wild-type and Pank2 mutant mice were fed pantothenic acid-deficient diets and were monitored for general health, fertility and movement compared with animals on control diets over time. Mice of both genotypes on PAdeficient diets exhibited poor grooming, greying of fur and decreased body weight. With PA deprivation, wild-type mice manifested azoospermia (a phenotype also seen in Pank2 mice) as well as a movement disorder with a low-lying pelvis and slow steps. Rear limbs appeared to drag and occasionally extended into unnatural postures for 16-17 s duration, possibly indicative of dystonia. Movement disruption probably also occurs in PA-deprived Pank2 mutant mice, but they died precipitously before undergoing detailed analysis. Remarkably, restoration of dietary PA led to recovery of general health and grooming, weight gain, reversal of the movement disorder, and reappearance of mature sperm within 4 weeks. This study confirms the primacy of PA metabolism in the mechanism of disease in PKAN. PA deprivation provides a useful phenocopy for PKAN and allows us to test pharmacological and other interventional strategies in the treatment of this devastating disease.

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“…Neurodegeneration with brain iron accumulation (NBIA), formerly known as Hallervorden-Spatz disease, often begins within the first few years of life and leads to progressive impairment of movement, speech, and cognition (Dooling et al, 1974;Swaiman, 1991). Iron accumulation in the globus pallidus can be visualized by magnetic resonance imaging (MRI), often in a characteristic pattern referred to as the "eye-of-the-tiger" sign (Hayflick et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Altered Neuronal Mitochondrial Coenzyme A Synthesis in Neurodegeneration with Brain Iron Accumulation Caused by Abnormal Processing, Stability, and Catalytic Activity of Mutant Pantothenate Kinase 2

Kotzbauer¹,

Truax²,

Trojanowski³

et al. 2005

J. Neurosci.

136

126

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Mutations in the pantothenate kinase 2 (PANK2) gene have been identified in patients with neurodegeneration with brain iron accumulation (NBIA; formerly Hallervorden-Spatz disease). However, the mechanisms by which these mutations cause neurodegeneration are unclear, especially given the existence of multiple pantothenate kinase genes in humans and multiple PanK2 transcripts with potentially different subcellular localizations. We demonstrate that PanK2 protein is localized to mitochondria of neurons in human brain, distinguishing it from other pantothenate kinases that do not possess mitochondrial-targeting sequences. PanK2 protein translated from the most 5Ј start site is sequentially cleaved at two sites by the mitochondrial processing peptidase, generating a long-lived 48 kDa mature protein identical to that found in human brain extracts. The mature protein catalyzes the initial step in coenzyme A (CoA) synthesis but displays feedback inhibition in response to species of acyl CoA rather than CoA itself. Some, but not all disease-associated point mutations result in significantly reduced catalytic activity. The most common mutation, G521R, results in marked instability of the intermediate PanK2 isoform and reduced production of the mature isoform. These results suggest that NBIA is caused by altered neuronal mitochondrial lipid metabolism caused by mutations disrupting PanK2 protein levels and catalytic activity.

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Hallervorden-Spatz Syndrome

Cited by 244 publications

References 35 publications

Dityrosine Cross-linking Promotes Formation of Stable α-Synuclein Polymers

Dityrosine Cross-linking Promotes Formation of Stable α-Synuclein Polymers

Deprivation of pantothenic acid elicits a movement disorder and azoospermia in a mouse model of pantothenate kinase‐associated neurodegeneration

Altered Neuronal Mitochondrial Coenzyme A Synthesis in Neurodegeneration with Brain Iron Accumulation Caused by Abnormal Processing, Stability, and Catalytic Activity of Mutant Pantothenate Kinase 2

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