The clinical and pathological spectrum of Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy): a reappraisal

Daniel, S. E.; Bruin, Veralice Meireles Sales de; Lees, Andrew J.

doi:10.1093/brain/118.3.759

Cited by 257 publications

(164 citation statements)

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“…By RNase mapping experiments, we have shown that exon 3 was skipped in 4 to 6% of the total HTH mRNA population in normal adrenal medulla, a proportion similar to that of the previously described HTH-3 and -4 mRNA species (11,12). These novel mRNA species were unusually abundant (5) in adrenal medulla of patients suffering from progressive supranuclear palsy (PSP), which is a severe neurodegenerative disease predominantly characterized by an alteration of the catecholaminergic neurons within the basal ganglia (13). The novel mRNA species encode putative HTH proteins lacking the 74 amino acids of the exon 3.…”

supporting

confidence: 56%

A Human Tyrosine Hydroxylase Isoform Associated with Progressive Supranuclear Palsy Shows Altered Enzymatic Activity

Bodeau-Péan¹,

Ravassard²,

Neuner-Jehle³

et al. 1999

Journal of Biological Chemistry

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A novel human tyrosine hydroxylase (HTH) messenger RNA subgroup generated by alternative splicing and characterized by the absence of the third exon was recently identified. The corresponding putative protein lacks 74 amino acids including Ser 31 and Ser 40 , two major phosphorylation sites implicated in the regulation of HTH activity. These mRNA species are detected in adrenal medulla and are overexpressed in patients suffering from progressive supranuclear palsy, a neurodegenerative disease mostly affecting catecholaminergic neurons of the basal ganglia.In the present work, an HTH protein isoform lacking exon 3 was identified in human adrenal medulla. For this purpose, an antibody was raised against the HTH exon 3. The effect of the removal of exon 3 on the enzymatic activity of HTH was studied in vitro by comparing a purified recombinant fusion protein without exon 3 (glutathione S-transferase (GST)-HTH⌬3) to the equivalent protein containing exon 3 (GST-HTH3). In initial velocity conditions, GST-HTH⌬3 has 30% of the maximal velocity of GST-HTH3. Moreover, the skipping of exon 3 results in the absence of activation of GST-HTH by heparin and increases by 10-fold the retroinhibition constant for dopamine, demonstrating the involvement of exon 3 in the regulation of HTH enzymatic activity. The identification of a variably expressed HTH isoform that lacks an exon implicated in activity regulation supports the view that HTH alternative splicing contributes to the functional diversity within the catecholaminergic system and may be implicated in some neurological diseases. Tyrosine hydroxylase (TH)1 has been the subject of extensive investigation, largely because it catalyzes the rate-limiting step in the biosynthesis of catecholamines. The regulation of the TH level and of its enzymatic activity is thus a major mechanism for controlling the amount of these important amines in blood and synapses. TH is regulated by almost all possible mechanisms of transcriptional and post-transcriptional control including regulation of the transcription rate, alternative splicing of the premessenger, variable stability of the mRNA, translational control, and modulation of the enzymatic activity (1). Recently, it has been shown that some human TH (HTH) gene sequence variants are associated with abnormal TH enzymatic activity and may be involved in some neurodegenerative diseases. Indeed, point mutations in the coding sequence of HTH have been found that decrease the activity of the enzyme in patients with L-DOPA-responsive dystonia (2) and inherited juvenile L-DOPA-responsive parkinsonism (3). There is also emerging evidence that alternative splicing of TH premessenger RNA may have physiological and even pathological consequences (4, 5). Initially, four HTH mRNA variants generated by alternative splicing were cloned and characterized by (i) the differential use of two splicing donor sites within exon 1 and (ii) the differential inclusion of exon 2 (4, 6, 7). All four HTH species are present in human catecholaminergic tissues (8, 9)....

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supporting

confidence: 56%

A Human Tyrosine Hydroxylase Isoform Associated with Progressive Supranuclear Palsy Shows Altered Enzymatic Activity

Bodeau-Péan¹,

Ravassard²,

Neuner-Jehle³

et al. 1999

Journal of Biological Chemistry

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“…Conversely, in some atypical parkinsonian syndromes, such as PSP, mainly striatal neurons degenerate (Daniel et al, 1995;Burn and Lees, 2002). Reduced activity of complex I of the mitochondrial respiratory chain has been implicated in both these clinical conditions (Schapira et al, 1990;Dawson and Dawson, 2003;Höglinger et al, 2005Höglinger et al, , 2006Di Filippo et al, 2006;Sherer et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, PSP is an atypical parkinsonian syndrome characterized by dorsorostral midbrain atrophy associated with severe neuronal loss in the substantia nigra, loss of striatal GABAergic projecting spiny neurons, and cerebral tau protein pathology (Daniel et al, 1995;Burn and Lees, 2002;Pearce, 2007).…”

Section: Introductionmentioning

confidence: 99%

Electrophysiology and Pharmacology of Striatal Neuronal Dysfunction Induced by Mitochondrial Complex I Inhibition

Costa¹,

Belcastro²,

Tozzi³

et al. 2008

J. Neurosci.

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Reduced activity of the mitochondrial respiratory chain and in particular of complex I is implicated not only in the etiology of Parkinson's disease but also in other forms of parkinsonism in which striatal neurodegeneration occurs, such as progressive supranuclear palsy.The pesticide rotenone inhibits mitochondrial complex I and reproduces features of these basal ganglia neurological disorders in animal models. We have characterized the electrophysiological effects of rotenone in the striatum as well as potential neuroprotective strategies to counteract the detrimental effects of this neurotoxin. We found that rotenone causes a dose-dependent and irreversible loss of the corticostriatal field potential amplitude, which was related to the development of a membrane depolarization/inward current in striatal spiny neurons, coupled to an increased release of both excitatory amino acids and dopamine (DA).In particular, we have investigated whether glutamate, DA, and GABA systems might represent possible targets for neuroprotection against rotenone-induced striatal neuronal dysfunction. Interestingly, whereas modulation of glutamatergic transmission was not neuroprotective, blockade of D 2 -like but not D 1 -like DA receptors significantly reduced the rotenone-induced effects via a GABA-mediated mechanism. In addition, because antiepileptic drugs (AEDs) modulate multiple transmitter systems, we have analyzed the possible neuroprotective effects of some AEDs against rotenone. We found that carbamazepine, unlike other tested AEDs, exerts a potent neuroprotective action against rotenone-induced striatal neuronal dysfunction. This neuroprotection was observed at therapeutically relevant concentrations requiring endogenous GABA. Differential targeting of GABAergic transmission may represent a possible therapeutic strategy against basal ganglia neurodegenerative disorders involving mitochondrial complex I dysfunction.

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“…We and others have identified alternative clinical phenotypes7, 8 related to PSP pathology in relatively small case series. This led to the description of 2 distinct PSP non‐RS clinical phenotypes by Williams and colleagues, PSP‐parkinsonism (PSP‐P)9 and pure akinesia with gait freezing (PAGF) 10.…”

mentioning

confidence: 88%

Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype

Jabbari

Woodside

Tan

et al. 2018

Annals of Neurology

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ObjectiveThe basis for clinical variation related to underlying progressive supranuclear palsy (PSP) pathology is unknown. We performed a genome‐wide association study (GWAS) to identify genetic determinants of PSP phenotype.MethodsTwo independent pathological and clinically diagnosed PSP cohorts were genotyped and phenotyped to create Richardson syndrome (RS) and non‐RS groups. We carried out separate logistic regression GWASs to compare RS and non‐RS groups and then combined datasets to carry out a whole cohort analysis (RS = 367, non‐RS = 130). We validated our findings in a third cohort by referring to data from 100 deeply phenotyped cases from a recent GWAS. We assessed the expression/coexpression patterns of our identified genes and used our data to carry out gene‐based association testing.ResultsOur lead single nucleotide polymorphism (SNP), rs564309, showed an association signal in both cohorts, reaching genome‐wide significance in our whole cohort analysis (odds ratio = 5.5, 95% confidence interval = 3.2–10.0, p = 1.7 × 10−9). rs564309 is an intronic variant of the tripartite motif‐containing protein 11 (TRIM11) gene, a component of the ubiquitin proteasome system (UPS). In our third cohort, minor allele frequencies of surrogate SNPs in high linkage disequilibrium with rs564309 replicated our findings. Gene‐based association testing confirmed an association signal at TRIM11. We found that TRIM11 is predominantly expressed neuronally, in the cerebellum and basal ganglia.InterpretationOur study suggests that the TRIM11 locus is a genetic modifier of PSP phenotype and potentially adds further evidence for the UPS having a key role in tau pathology, therefore representing a target for disease‐modifying therapies. Ann Neurol 2018;84:485–496

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The clinical and pathological spectrum of Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy): a reappraisal

Cited by 257 publications

References 0 publications

A Human Tyrosine Hydroxylase Isoform Associated with Progressive Supranuclear Palsy Shows Altered Enzymatic Activity

A Human Tyrosine Hydroxylase Isoform Associated with Progressive Supranuclear Palsy Shows Altered Enzymatic Activity

Electrophysiology and Pharmacology of Striatal Neuronal Dysfunction Induced by Mitochondrial Complex I Inhibition

Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype

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