Inhibiting pathologically active ADAM10 rescues synaptic and cognitive decline in Huntington’s disease

Vezzoli, Elena; Caron, Ilaria; Talpo, Francesca; Besusso, Dario; Conforti, Paola; Battaglia, Elisa; Sogne, Elisa; Falqui, Andrea; Petricca, Lara; Verani, Margherita; Martufi, Paola; Caricasole, Andrea; Bresciani, Alberto; Cecchetti, Ottavia; Cervo, Pia Rivetti di Val; Sancini, Giulio; Rieß, Olaf; Nguyen, Hoa Huu Phuc; Seipold, Lisa; Säftig, Paul; Biella, Gerardo; Cattaneo, Elena; Zuccato, Chiara

doi:10.1172/jci120616

Cited by 39 publications

(50 citation statements)

References 33 publications

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“…Therefore, increased mEPSC frequency in zQ175:CK2α’ (+/-) mice cannot be attributed to a greater number of neurons within the striatum. However, we observed significant increases in the levels of synaptic proteins like the scaffold protein Dlg4 (PSD-95), and Ppp1rb1 (dopamine- and cAMP-regulated neuronal phosphoprotein DARPP-32), a key regulator of the electrophysiological responses in striatal neurons (Fienberg et al 1998, Vezzoli et al 2019) ( Fig. S5C ).…”

Section: Resultsmentioning

confidence: 97%

“…Improved strength of glutamatergic synaptic transmission is often related to improved motor control and cognitive processes in HD mouse models (Smith-Dijak, Sepers, and Raymond 2019, Vezzoli et al 2019). To assess the impact of CK2α’ haploinsufficiency on motor function, we conducted a series of motor tests including accelerating rotarod and beam walk comparing 3-month (pre-symptomatic) and 12-month-old (symptomatic) mice ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington’s disease

Zarate

Cuccu

et al. 2020

Preprint

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Huntington′s Disease (HD) is a neurodegenerative disorder caused a polyglutamine expansion in the HTT protein. This mutation causes HTT misfolding and aggregation, preferentially affecting neurons of the basal ganglia. Other aggregation-prone proteins like alpha-synuclein (α-syn), mostly associated with Parkinson′s disease (PD), has recently been involved in motor deficits in HD, but its mechanism of action is unknown. Here we showed that α-syn serine 129 phosphorylation (α-syn-pS129), a posttranslational modification linked to α-synucleinopathy, is highly phosphorylated in the brain of symptomatic zQ175 HD mice. We demonstrated that such phosphorylation is mediated by Protein Kinase CK2 alpha prime (CK2α′), which is preferentially induced in striatal neurons in HD. Knocking out one allele of CK2α′ in zQ175 mice decreased α-syn-pS129 in the striatum and ameliorated several HD-like symptoms including neuroinflammation, transcriptional alterations, excitatory synaptic transmission dysfunction and motor deficits. Our data suggests CK2α′-mediated synucleinopathy as a key molecular mechanism for striatal neurons degeneration in HD.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington’s disease

Zarate

Cuccu

et al. 2020

Preprint

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“…However, there is no hearing deficit in the absence of the Id1 gene, and the reason for this might be compensatory effects by other Id s like Id3 , which has a similar expression pattern as Id1 in the cochlea [75, 76]. Adam10 is abundantly expressed in the brain and is linked to epilepsy, Alzheimer’s disease, Hunting’s disease, and developmental disorder Fragile X syndrome because of its role in regulating the activity of excitatory synapses [104, 105]. Adam10 is also expressed in the cochlea and vestibule, and inhibition of Adam10 after HC loss increases the proliferation of SCs in the vestibular system [77–79].…”

Section: Discussionmentioning

confidence: 99%

Age-related transcriptome changes in Sox2+ supporting cells in the mouse cochlea

et al. 2019

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BackgroundInner ear supporting cells (SCs) in the neonatal mouse cochlea are a potential source for hair cell (HC) regeneration, but several studies have shown that the regeneration ability of SCs decreases dramatically as mice age and that lost HCs cannot be regenerated in adult mice. To better understand how SCs might be better used to regenerate HCs, it is important to understand how the gene expression profile changes in SCs at different ages.MethodsHere, we used Sox2GFP/+ mice to isolate the Sox2+ SCs at postnatal day (P)3, P7, P14, and P30 via flow cytometry. Next, we used RNA-seq to determine the transcriptome expression profiles of P3, P7, P14, and P30 SCs. To further analyze the relationships between these age-related and differentially expressed genes in Sox2+ SCs, we performed gene ontology (GO) analysis.ResultsConsistent with previous reports, we also found that the proliferation and HC regeneration ability of isolated Sox2+ SCs significantly decreased as mice aged. We identified numerous genes that are enriched and differentially expressed in Sox2+ SCs at four different postnatal ages, including cell cycle genes, signaling pathway genes, and transcription factors that might be involved in regulating the proliferation and HC differentiation ability of SCs. We thus present a set of genes that might regulate the proliferation and HC regeneration ability of SCs, and these might serve as potential new therapeutic targets for HC regeneration.ConclusionsIn our research, we found several genes that might play an important role in regulating the proliferation and HC regeneration ability of SCs. These datasets are expected to serve as a resource to provide potential new therapeutic targets for regulating the ability of SCs to regenerate HCs in postnatal mammals.

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“…SFRP1 was also shown to be anti-apoptotic in fibroblasts through regulation of several apoptosis-related genes [143]. Although whether it has a neuronal survival function per se is yet unclear, inhibition of pathologically active ADAM10 has been recently shown to rescue synaptic disruption and cognitive decline in neurons of Huntington's disease mice [26]. Loss of SFRP1 activity could also impact Wnt signaling and give rise to other systemic problems.…”

Section: A View Of Sfrp1 In Ad-mechanisms Benefits and Risksmentioning

confidence: 99%

“…The ectodomain cleaving sheddase ADAM10 has a number of important brain substrates such as Notch [20] (and its ligands [21]) and N-cadherin [20,22], as well as many different functions [23]. It is essential for neurodevelopment [24] and its aberrant activity has been linked to several neurological diseases other than AD [25,26]. There is also some evidence for a genetic link between ADAM10 polymorphism and sporadic AD [27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Enhancing α-secretase Processing for Alzheimer’s Disease—A View on SFRP1

Tang

2020

Brain Sciences

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Amyloid β (Aβ) peptides generated via sequential β- and γ-secretase processing of the amyloid precursor protein (APP) are major etiopathological agents of Alzheimer’s disease (AD). However, an initial APP cleavage by an α-secretase, such as the a disintegrin and metalloproteinase domain-containing protein ADAM10, precludes β-secretase cleavage and leads to APP processing that does not produce Aβ. The latter appears to underlie the disease symptom-attenuating effects of a multitude of experimental therapeutics in AD animal models. Recent work has indicated that an endogenous inhibitor of ADAM10, secreted-frizzled-related protein 1 (SFRP1), is elevated in human AD brains and associated with amyloid plaques in mouse AD models. Importantly, genetic or functional attenuation of SFRP1 lowered Aβ accumulation and improved AD-related histopathological and neurological traits. Given SFRP1′s well-known activity in attenuating Wnt signaling, which is also commonly impaired in AD, SFRP1 appears to be a promising therapeutic target for AD. This idea, however, needs to be addressed with care because of cancer enhancement potentials resulting from a systemic loss of SFRP1 activity, as well as an upregulation of ADAM10 activity. In this focused review, I shall discuss α-secretase-effected APP processing in AD with a focus on SFRP1, and explore the contrasting perspectives arising from the recent findings.

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Inhibiting pathologically active ADAM10 rescues synaptic and cognitive decline in Huntington’s disease

Cited by 39 publications

References 33 publications

CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington’s disease

CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington’s disease

Age-related transcriptome changes in Sox2+ supporting cells in the mouse cochlea

Enhancing α-secretase Processing for Alzheimer’s Disease—A View on SFRP1

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