iPSC-derived neurons profiling reveals GABAergic circuit disruption and acetylated α-tubulin defect which improves after iHDAC6 treatment in Rett syndrome

Landucci, Elisa; Brindisi, Margherita; Bianciardi, Laura; Catania, Lorenza; Daga, Sergio; Croci, Susanna; Frullanti, Elisa; Fallerini, Chiara; Butini, Stefania; Brogi, Simone; Furini, Simone; Melani, Riccardo; Molinaro, Angelo; Lorenzetti, Flaminia C; Imperatore, Valentina; Amabile, Sonia; Mariani, Jessica; Mari, Francesca; Ariani, Francesca; Pizzorusso, Tommaso; Pinto, Anna Maria; Vaccarino, Flora M.; Renieri, Alessandra; Campiani, Giuseppe; Meloni, Ilaria

doi:10.1016/j.yexcr.2018.05.001

Cited by 42 publications

(50 citation statements)

References 64 publications

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“…Indeed, we have recently shown that in the absence of MeCP2, microtubule polymerization from centrosomes is impaired (Bergo et al , ). In good accordance, a reduction in microtubule stability associated with decreased α‐tubulin acetylation, caused by increased levels of HDAC6, was reported (Xu et al , ; Gold et al , ; Delépine et al , ; Landucci et al , ). Real‐time RT–PCR suggested that a post‐transcriptional mechanism is involved in the observed HDAC6 upregulation (Delépine et al , ) and our unpublished data confirm that Hdac6 mRNA levels are not perturbed in the Mecp2 null brain.…”

Section: Discussionsupporting

confidence: 71%

MECP2 mutations affect ciliogenesis: a novel perspective for Rett syndrome and related disorders

et al. 2020

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Mutations in MECP2 cause several neurological disorders of which Rett syndrome (RTT) represents the best-defined condition. Although mainly working as a transcriptional repressor, MeCP2 is a multifunctional protein revealing several activities, the involvement of which in RTT remains obscure. Besides being mainly localized in the nucleus, MeCP2 associates with the centrosome, an organelle from which primary cilia originate. Primary cilia function as "sensory antennae" protruding from most cells, and a link between primary cilia and mental illness has recently been reported. We herein demonstrate that MeCP2 deficiency affects ciliogenesis in cultured cells, including neurons and RTT fibroblasts, and in the mouse brain. Consequently, the cilium-related Sonic Hedgehog pathway, which is essential for brain development and functioning, is impaired. Microtubule instability participates in these phenotypes that can be rescued by HDAC6 inhibition together with the recovery of RTT-related neuronal defects. Our data indicate defects of primary cilium as a novel pathogenic mechanism that by contributing to the clinical features of RTT might impact on proper cerebellum/brain development and functioning, thus providing a novel therapeutic target.

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Section: Discussionsupporting

confidence: 71%

MECP2 mutations affect ciliogenesis: a novel perspective for Rett syndrome and related disorders

et al. 2020

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“…Therefore, we suspect that HDAC6 inhibition under conditions lacking robust tau pathology might alter the acetylation status of non-tau HDAC6-dependent substrates (e.g., tubulin, cortactin, Hsp90) and thus restore axonal transport and MT-dependent trafficking, for example in the presence of Aβ (as we observed in the 5xFAD model) 50 . Indeed, loss or inhibition of HDAC6 was reported to stabilize MTs and improve axonal transport in nontauopathy syndromes including Charcot Marie Tooth (CMT) neuropathy 51,52 , amyotrophic lateral sclerosis (ALS) 53 , Rett syndrome 54 , and Aβ plaque deposition 19 .…”

Section: Discussionmentioning

confidence: 99%

An HDAC6-dependent surveillance mechanism suppresses tau-mediated neurodegeneration and cognitive decline

Trzeciakiewicz

Ajit²,

Tseng³

et al. 2020

Nat Commun

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Tauopathies including Alzheimer’s disease (AD) are marked by the accumulation of aberrantly modified tau proteins. Acetylated tau, in particular, has recently been implicated in neurodegeneration and cognitive decline. HDAC6 reversibly regulates tau acetylation, but its role in tauopathy progression remains unclear. Here, we identified an HDAC6-chaperone complex that targets aberrantly modified tau. HDAC6 not only deacetylates tau but also suppresses tau hyperphosphorylation within the microtubule-binding region. In neurons and human AD brain, HDAC6 becomes co-aggregated within focal tau swellings and human AD neuritic plaques. Using mass spectrometry, we identify a novel HDAC6-regulated tau acetylation site as a disease specific marker for 3R/4R and 3R tauopathies, supporting uniquely modified tau species in different neurodegenerative disorders. Tau transgenic mice lacking HDAC6 show reduced survival characterized by accelerated tau pathology and cognitive decline. We propose that a HDAC6-dependent surveillance mechanism suppresses toxic tau accumulation, which may protect against the progression of AD and related tauopathies.

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“…To characterize the biological mechanisms implicated in disease pathogenesis, we established and characterized a human neuronal model based on genetic reprogramming of patient fibroblasts into induced Pluripotent Stem Cells (iPSCs) [ 14 – 16 ]. iPSCs are a valuable source of patient-derived cells like neurons, which represent the most relevant cell type for studying disease mechanisms as well as for testing innovative therapeutic approaches, such as gene editing.…”

Section: Introductionmentioning

confidence: 99%

High rate of HDR in gene editing of p.(Thr158Met) MECP2 mutational hotspot

et al. 2020

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Rett syndrome is a progressive neurodevelopmental disorder which affects almost exclusively girls, caused by variants in MECP2 gene. Effective therapies for this devastating disorder are not yet available and the need for tight regulation of MECP2 expression for brain to properly function makes gene replacement therapy risky. For this reason, gene editing with CRISPR/Cas9 technology appears as a preferable option for the development of new therapies. To study the disease, we developed and characterized a human neuronal model obtained by genetic reprogramming of patient-derived primary fibroblasts into induced Pluripotent Stem Cells. This cellular model represents an important source for our studies, aiming to correct MECP2 variants in neurons which represent the primarily affected cell type. We engineered a gene editing toolkit composed by a two-plasmid system to correct a hotspot missense variant in MECP2 , c.473 C > T (p.(Thr158Met)). The first construct expresses the variant-specific sgRNA and the Donor DNA along with a fluorescent reporter system. The second construct brings Cas9 and targets for auto-cleaving, to avoid long-term Cas9 expression. NGS analysis on sorted cells from four independent patients demonstrated an exceptionally high editing efficiency, with up to 80% of HDR and less than 1% of indels in all patients, outlining the relevant potentiality of the approach for Rett syndrome therapy.

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iPSC-derived neurons profiling reveals GABAergic circuit disruption and acetylated α-tubulin defect which improves after iHDAC6 treatment in Rett syndrome

Cited by 42 publications

References 64 publications

MECP2 mutations affect ciliogenesis: a novel perspective for Rett syndrome and related disorders

MECP2 mutations affect ciliogenesis: a novel perspective for Rett syndrome and related disorders

An HDAC6-dependent surveillance mechanism suppresses tau-mediated neurodegeneration and cognitive decline

High rate of HDR in gene editing of p.(Thr158Met) MECP2 mutational hotspot

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