Fragile X-associated tremor ataxia syndrome with co-occurrent progressive supranuclear palsy-like neuropathology

Abstract Co-occurrence of multiple neuropathologic changes is a common phenomenon, most prominently seen in Alzheimer’s disease (AD) and Parkinson’s disease (PD), complicating clinical diagnosis and patient management. Reports of co-occurring pathological processes are emerging in the group of genetically defined repeat-associated non-AUG (RAN)-translation related diseases. Here we report a case of Fragile X-associated tremor-ataxia syndrome (FXTAS) with widespread and abundant nuclear inclusions of the RAN-translation related FMRpolyG-peptide. In addition, we describe prominent neuronal and glial tau pathology representing changes seen in progressive supranuclear palsy (PSP). The highest abundance of the respective pathological changes was seen in distinct brain regions indicating an incidental, rather than causal correlation.

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Near-cognate initiation generates FMRpolyG from CGG repeats in Fragile X associated Tremor Ataxia Syndrome

10.1101/2020.10.19.345736 ◽

2020 ◽

Author(s):

Yuan Zhang ◽

M. Rebecca Glineburg ◽

Venkatesha Basrur ◽

Kevin Conlon ◽

Deborah A. Hall ◽

...

Keyword(s):

Fragile X ◽

Model Systems ◽

Initiation Factor ◽

Amino Terminal ◽

Human Samples ◽

Cgg Repeats ◽

Cellular Environment ◽

Ataxia Syndrome ◽

Signature Peptides ◽

Ran Translation

AbstractRepeat associated non-AUG (RAN) translation of FMR1 5’ UTR CGG repeats produces toxic homo-polymeric proteins that accumulate within ubiquitinated inclusions in Fragile X-associated tremor/ataxia syndrome (FXTAS) patient brains and model systems. The most abundant RAN product, FMRpolyG, initiates predominantly at an ACG codon located just 5’ to the repeat. Methods to accurately measure FMRpolyG in FXTAS patients are lacking. Here we used data dependent acquisition (DDA) and parallel reaction monitoring (PRM) mass spectrometry coupled with stable isotope labeled standard peptides (SIS) to identify potential signature FMRpolyG fragments in patient cells and tissues. Following immunoprecipitation (IP) enrichment, we detected FMRpolyG signature peptides by PRM in transfected cells, FXTAS human samples and patient derived stem cells, but not in controls. Surprisingly, we identified two amino-terminal peptides: one beginning with methionine (Ac-MEAPLPGGVR) initiating at an ACG, and a second beginning with threonine (Ac-TEAPLPGGVR), initiating at a GUG. Abundance of the threonine peptide was enhanced relative to the methionine peptide upon activation of the integrated stress response. In addition, loss of the eIF2 alternative factor, eIF2A, or enhanced expression of initiation factor eIF1, preferentially suppressed GUG initiated FMRpolyG synthesis. These data demonstrate that FMRpolyG is quantifiable in human samples and that RAN translation on FMR1 initiates at specific near cognate codons dependent on available initiation factors and cellular environment.

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Mechanistic Convergence Across Initiation Sites for RAN Translation in Fragile X Associated Tremor Ataxia Syndrome

SSRN Electronic Journal ◽

10.2139/ssrn.3825862 ◽

2021 ◽

Author(s):

Yuan Zhang ◽

M. Rebecca Glineburg ◽

Venkatesha Basrur ◽

Kevin P. Conlon ◽

Shannon E. Wright ◽

...

Keyword(s):

Fragile X ◽

Ataxia Syndrome ◽

Ran Translation

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RAN translation at CGG repeats induces ubiquitin proteasome system impairment in models of fragile X-associated tremor ataxia syndrome

Human Molecular Genetics ◽

10.1093/hmg/ddv165 ◽

2015 ◽

Vol 24 (15) ◽

pp. 4317-4326 ◽

Cited By ~ 54

Author(s):

Seok Yoon Oh ◽

Fang He ◽

Amy Krans ◽

Michelle Frazer ◽

J. Paul Taylor ◽

...

Keyword(s):

Fragile X ◽

Ubiquitin Proteasome System ◽

Cgg Repeats ◽

Ubiquitin Proteasome ◽

Ataxia Syndrome ◽

Ran Translation

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CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome

Science Advances ◽

10.1126/sciadv.abd9440 ◽

2021 ◽

Vol 7 (3) ◽

pp. eabd9440

Author(s):

Sefan Asamitsu ◽

Yasushi Yabuki ◽

Susumu Ikenoshita ◽

Kosuke Kawakubo ◽

Moe Kawasaki ◽

...

Keyword(s):

Therapeutic Strategy ◽

Aminolevulinic Acid ◽

Fragile X ◽

Protoporphyrin Ix ◽

Neuronal Dysfunction ◽

Cgg Repeat ◽

Repeat Expansions ◽

Ataxia Syndrome ◽

And Behavior ◽

Ran Translation

Fragile X-related tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease caused by CGG triplet repeat expansions in FMR1, which elicit repeat-associated non-AUG (RAN) translation and produce the toxic protein FMRpolyG. We show that FMRpolyG interacts with pathogenic CGG repeat-derived RNA G-quadruplexes (CGG-G4RNA), propagates cell to cell, and induces neuronal dysfunction. The FMRpolyG polyglycine domain has a prion-like property, preferentially binding to CGG-G4RNA. Treatment with 5-aminolevulinic acid, which is metabolized to protoporphyrin IX, inhibited RAN translation of FMRpolyG and CGG-G4RNA–induced FMRpolyG aggregation, ameliorating aberrant synaptic plasticity and behavior in FXTAS model mice. Thus, we present a novel therapeutic strategy to target G4RNA prionoids.

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PET markers of tau and neuroinflammation are co-localized in progressive supranuclear palsy

10.1101/19010702 ◽

2019 ◽

Cited By ~ 2

Author(s):

Maura Malpetti ◽

Luca Passamonti ◽

Timothy Rittman ◽

P. Simon Jones ◽

Patricia Vázquez Rodríguez ◽

...

Keyword(s):

Progressive Supranuclear Palsy ◽

Microglial Activation ◽

Principal Component ◽

Brain Regions ◽

Clinical Severity ◽

Binding Potential ◽

Tau Pathology ◽

Richardson’S Syndrome ◽

The Relationship

AbstractBackgroundProgressive Supranuclear Palsy (PSP) is associated with tau-protein aggregation and neuroinflammation, but it remains unclear whether these pathogenic processes are related in vivo.ObjectivesWe examined the relationship between tau pathology and microglial activation using [18F]AV-1451 (indexing tau burden) and [11C]PK11195 (microglial activation) PET in n=17 patients with PSP-Richardson’s syndrome.MethodsNon-displaceable binding potential (BPND) for each ligand was quantified in 83 regions of interest (ROIs). [18F]AV-1451 and [11C]PK11195 BPND values were correlated across all ROIs. The anatomical patterns of [18F]AV-1451 and [11C]PK11195 binding co-localization was determined across sets of regions derived from principal component analyses (PCAs). Finally, PCA-derived brain patterns of tau pathology and neuroinflammation were linked to clinical severity.Results[18F]AV-1451 and [11C]PK11195 binding were positively related across all ROIs (r=0.577, p<0.0001). PCAs identified four components for each ligand, reflecting the relative expression of tau pathology or neuroinflammation in distinct groups of brain regions. Positive associations between [18F]AV-1451 and [11C]PK11195 components were found in sub-cortical (r=0.769, p<0.0001) and cortical components(r=0.836, p<0.0001). PCA-derived components reflecting tau burden (r=0.599, p=0.011) and neuroinflammation (r=0.713, p=0.001) in sub-cortical areas related to disease severity.ConclusionsWe show that tau pathology and neuroinflammation co-localize in PSP, and that individual differences in subcortical tau pathology and neuroinflammation are linked to clinical severity. Although longitudinal studies are needed to determine how these molecular pathologies are causally linked, we suggest that the combination of tau- and immune-oriented strategies may be useful for effective disease-modifying treatments in PSP.

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Neuropathology of RAN translation proteins in Fragile X-associated Tremor/Ataxia Syndrome

10.1101/672444 ◽

2019 ◽

Cited By ~ 1

Author(s):

Amy Krans ◽

Geena Skariah ◽

Yuan Zhang ◽

Bryana Bayly ◽

Peter K. Todd

Keyword(s):

Hippocampal Neurons ◽

Neurodegenerative Disorder ◽

Fragile X ◽

Antisense Strand ◽

Common Component ◽

Cgg Repeat ◽

Neuronal Nuclei ◽

Sense Strand ◽

Ataxia Syndrome ◽

Ran Translation

AbstractCGG repeat expansions in FMR1 cause the neurodegenerative disorder Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). Ubiquitinated neuronal intranuclear inclusions (NIIs) are the neuropathological hallmark of FXTAS. Both sense strand derived CGG repeats and antisense strand derived CCG repeats support non-AUG initiated (RAN) translation of homopolymeric proteins in potentially 6 different reading frames. However, the relative abundance of these proteins in FXTAS brains and their co-localization with each other and NIIs is lacking. Here we describe rater-blinded assessment of immunohistochemical and immunofluorescence staining with newly generated antibodies to different CGG RAN translation products in FXTAS and control brains as well as co-staining with ubiquitin, p62/SQSTM1, and ubiquilin 2. We find that both FMRpolyG and a second CGG repeat derived RAN translation product, FMRpolyA, accumulate in aggregates in FXTAS brains. FMRpolyG is a near-obligate component of both ubiquitin-positive and p62-positive NIIs in FXTAS, with occurrence of aggregates in 20% of all hippocampal neurons and >90% of all inclusions. A subset of these inclusions also stain positive for the ALS/FTD associated protein ubiquilin 2. Ubiquitinated inclusions and FMRpolyG+ aggregates are rarer in cortex and cerebellum. Intriguingly, FMRpolyG staining is also visible in control neuronal nuclei. In contrast to FMRpolyG, staining for FMRpolyA and CCG antisense derived RAN translation products were less abundant and were infrequent components of FMRpolyG+ inclusions. In conclusion, RAN translated FMRpolyG is a common component of ubiquitin and p62 positive inclusions in FXTAS patient brains.

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Syntaxins 6 and 8 facilitate tau into secretory pathways

Biochemical Journal ◽

10.1042/bcj20200664 ◽

2021 ◽

Author(s):

Wei Siang Lee ◽

Daniel CS Tan ◽

Yuanyuan Deng ◽

Annika van Hummel ◽

Stefania Ippati ◽

...

Keyword(s):

Progressive Supranuclear Palsy ◽

Molecular Mechanisms ◽

Transmembrane Domain ◽

Brain Regions ◽

Tau Pathology ◽

Tail Region ◽

Secretory Pathways ◽

Donor Cells ◽

Neuronal Connections

Tau pathology initiates in defined brain regions and is known to spread along neuronal connections as symptoms progress in Alzheimer’s disease (AD) and other tauopathies. This spread requires the release of tau from donor cells, but the underlying molecular mechanisms remained unknown. Here, we established the interactome of the C-terminal tail region of tau and identified syntaxin 8 (STX8) as a mediator of tau release from cells. Similarly, we showed the syntaxin 6 (STX6), part of the same SNARE family as STX8 also facilitated tau release. STX6 was previously genetically linked to progressive supranuclear palsy (PSP), a tauopathy. Finally, we demonstrated that the transmembrane domain of STX6 is required and sufficient to mediate tau secretion. The differential role of STX6 and STX8 in alternative secretory pathways suggests association of tau with different secretory processes. Taken together, both syntaxins, STX6 and STX8, may contribute to AD and PSP pathogenesis by mediating release of tau from cells and facilitating pathology spreading.

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Neuropathology of RAN translation proteins in fragile X-associated tremor/ataxia syndrome

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0782-7 ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 7

Author(s):

Amy Krans ◽

Geena Skariah ◽

Yuan Zhang ◽

Bryana Bayly ◽

Peter K. Todd

Keyword(s):

Hippocampal Neurons ◽

Neurodegenerative Disorder ◽

Fragile X ◽

Antisense Strand ◽

Common Component ◽

Cgg Repeat ◽

Neuronal Nuclei ◽

Sense Strand ◽

Ataxia Syndrome ◽

Ran Translation

Abstract CGG repeat expansions in FMR1 cause the neurodegenerative disorder Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). Ubiquitinated neuronal intranuclear inclusions (NIIs) are the neuropathological hallmark of FXTAS. Both sense strand derived CGG repeats and antisense strand derived CCG repeats support non-AUG initiated (RAN) translation of homopolymeric proteins in potentially 6 different reading frames. However, the relative abundance of these proteins in FXTAS brains and their co-localization with each other and NIIs is lacking. Here we describe rater-blinded assessment of immunohistochemical and immunofluorescence staining with newly generated antibodies to different CGG RAN translation products in FXTAS and control brains as well as co-staining with ubiquitin, p62/SQSTM1, and ubiquilin 2. We find that both FMRpolyG and a second CGG repeat derived RAN translation product, FMRpolyA, accumulate in aggregates in FXTAS brains. FMRpolyG is a near-obligate component of both ubiquitin-positive and p62-positive NIIs in FXTAS, with occurrence of aggregates in 20% of all hippocampal neurons and > 90% of all inclusions. A subset of these inclusions also stain positive for the ALS/FTD associated protein ubiquilin 2. Ubiquitinated inclusions and FMRpolyG+ aggregates are rarer in cortex and cerebellum. Intriguingly, FMRpolyG staining is also visible in control neuronal nuclei. In contrast to FMRpolyG, staining for FMRpolyA and CCG antisense derived RAN translation products were less abundant and less frequent components of ubiquitinated inclusions. In conclusion, RAN translated FMRpolyG is a common component of ubiquitin and p62 positive inclusions in FXTAS patient brains.

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