Passive immunization against phosphorylated tau improves features of Huntington's disease pathology

Alpaugh, Melanie; Masnata, Maria; Jacquet, Aurélie de Rus; Lepinay, Eva; Denis, Hélèna L.; Saint-Pierre, Martine; Davies, Peter; Planel, Emmanuel; Cicchetti, Francesca

doi:10.1016/j.ymthe.2022.01.020

Cited by 17 publications

(9 citation statements)

References 117 publications

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“…Here, we find a time-dependent increase in Tau phosphorylation at only 4 of 26 identified sites which correspond to human S202, T205, T217, and S404 ( Fig 6A ). This is a remarkably specific signature of phosphorylation which corresponds to sites at which Tau is phosphorylated in the AD brain (S202 – CP13 70 , T205 – AT8 71 , and S404-PHF1 72 ) as well as CSF biomarkers for AD progression (T217) 73 . To validate these data, we treated hTau-KI neurons with iBEp and then fixed and stained these neurons.…”

Section: Resultsmentioning

confidence: 99%

Dysregulation of neuroproteasomes by ApoE isoforms drives endogenous Tau aggregation

Paradise

Sabu

Bafia

et al. 2022

Preprint

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Neuronal membrane proteasomes (NMPs) are a functionally transmembrane subset of 20S proteasomes that degrade newly synthesized proteins. To date, the molecular composition of NMPs is undefined, and moreover, whether NMPs can influence any aspect of protein aggregation with relevance to neurodegenerative disorders remains unexplored. Using a Cre-dependent conditional knock-in mouse line to endogenously tag the proteasome, we find that NMPs co-purify with ApoE. We discover that NMP membrane localization is differentially modulated by ApoE isoforms (E4<E3<E2)in vitro,in vivo, and in human postmortem samples. This isoform-dependent change in NMP localization inversely correlates with the risk that ApoE isoforms pose for Alzheimer’s Disease. ApoE4-dependent reduction of NMP localization is strongest in brain regions selectively vulnerable to neurodegeneration. We synthesized selective NMP-specific inhibitors and discovered that NMP inhibition induces aggregation of endogenous and newly synthesized mouse and human Tau isoforms, without the need for seeding or pathogenic mutations. We posit that newly synthesized Tau is exceptionally susceptible to aggregation due to NMP dysfunction. Stereotactic injection of NMP inhibitorsin vivoinduces aggregation, phosphorylation, somatodendritic mislocalization and pathology of endogenous newly synthesized Tau. Finally, using ApoE-KI/hTau-KI crosses, we find that ApoE isoforms differentially shift the aggregation threshold for Tau. Overall, our data define NMPs as a pivotal proteostasis mechanism underlying the formation of endogenous Tau aggregates, which is directly regulated by the largest genetic risk factor for late-onset Alzheimer’s Disease.

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Section: Resultsmentioning

confidence: 99%

Dysregulation of neuroproteasomes by ApoE isoforms drives endogenous Tau aggregation

Paradise

Sabu

Bafia

et al. 2022

Preprint

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“…Interestingly, lesions formed by other pathogenic proteins, such as tau and α-synuclein, are also present in HD patient brains ( Jellinger, 1998 ; Charles et al, 2000 ) and appear in fetal graft tissue ( Cisbani et al, 2017 ; Ornelas et al, 2020 ), suggesting common pathways driving protein aggregation in these diseases. Anti-tau antibody treatment improves motor and cognitive performance in HD mice expressing mHTT ex1 ( Alpaugh et al, 2022 ), suggesting active involvement of tau pathology in HD neuropathogenesis. Evidence for co-aggregation of mHTT proteins with other amyloidogenic proteins such as Aβ ( Hartlage-Rübsamen et al, 2019 ) and TDP-43 ( Coudert et al, 2019 ) suggests that heterotypic cross-seeding might also contribute to disease pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Hunting for the cause: Evidence for prion-like mechanisms in Huntington’s disease

et al. 2022

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The hypothesis that pathogenic protein aggregates associated with neurodegenerative diseases spread from cell-to-cell in the brain in a manner akin to infectious prions has gained substantial momentum due to an explosion of research in the past 10–15 years. Here, we review current evidence supporting the existence of prion-like mechanisms in Huntington’s disease (HD), an autosomal dominant neurodegenerative disease caused by expansion of a CAG repeat tract in exon 1 of the huntingtin (HTT) gene. We summarize information gained from human studies and in vivo and in vitro models of HD that strongly support prion-like features of the mutant HTT (mHTT) protein, including potential involvement of molecular features of mHTT seeds, synaptic structures and connectivity, endocytic and exocytic mechanisms, tunneling nanotubes, and nonneuronal cells in mHTT propagation in the brain. We discuss mechanisms by which mHTT aggregate spreading and neurotoxicity could be causally linked and the potential benefits of targeting prion-like mechanisms in the search for new disease-modifying therapies for HD and other fatal neurodegenerative diseases.

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“…Of note, reducing a-synuclein levels augmented autophagy in R6/1 and N171-82Q animals and slowed down HD progression [ 129 , 131 ]. Moreover, an imbalance in tau isoform levels, prevalent in AD, with an enhanced three or four microtubule-binding repeats (4R/3R ratio) is enough to induce neurodegeneration [ 9 , 132 - 134 ]. This relationship is enhanced in HD mice due to splicing abnormalities and contributes to HD pathogenesis [ 9 , 132 , 134 ].…”

Section: Pathogenic Mechanisms In Hdmentioning

confidence: 99%

The Emerging Landscape of Natural Small-molecule Therapeutics for Huntington’s Disease

Bhat

Ahamad

Dar

et al. 2023

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Huntington’s disease (HD) is a rare and fatal neurodegenerative disorder with no disease modifying therapeutics. HD is characterized by extensive neuronal loss and is caused by the inherited expansion of the huntingtin (HTT) gene that encodes a toxic mutant HTT (mHTT) protein having expanded polyglutamine (polyQ) residues. Current HD therapeutics only offer symptomatic relief. Infact, Food and Drug Administration (FDA) approved two synthetic small-molecule VMAT2 inhibi-tors, tetrabenazine (1) and deutetrabenazine (2), for managing HD chorea and various other diseases in clinical trials. Therefore, the landscape of drug discovery programs for HD is evolving to discover disease-modifying HD therapeutics. Likewise, numerous natural products are being evaluated at different stages of clinical development and have shown the potential to ameliorate HD pathology. The inherent anti-inflammatory and antioxidant properties of natural products mitigate the mHTT-induced oxidative stress and neuroinflammation, improve mitochondrial functions, and augment the anti-apoptotic and pro-autophagic mechanisms for increased survival of neurons in HD. In this review, we have discussed HD pathogenesis and summarized the anti-HD clinical and pre-clinical natural products, focusing on their therapeutic effects and neuroprotective mechanisms.

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Passive immunization against phosphorylated tau improves features of Huntington's disease pathology

Cited by 17 publications

References 117 publications

Dysregulation of neuroproteasomes by ApoE isoforms drives endogenous Tau aggregation

Dysregulation of neuroproteasomes by ApoE isoforms drives endogenous Tau aggregation

Hunting for the cause: Evidence for prion-like mechanisms in Huntington’s disease

The Emerging Landscape of Natural Small-molecule Therapeutics for Huntington’s Disease

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