Insights into disease mechanisms and potential therapeutics for C9orf72-related amyotrophic lateral sclerosis/frontotemporal dementia

Gagliardi, Delia; Costamagna, Gianluca; Taiana, Michela; Andreoli, Luca; Biella, Fabio; Bersani, Margherita; Bresolin, Nereo; Comi, Giacomo Pietro; Corti, Stefania

doi:10.1016/j.arr.2020.101172

Cited by 7 publications

(7 citation statements)

References 274 publications

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“…The C9-HRE leads to several distinct pathogenic mechanisms, including C9orf72 protein loss-of function related to C9orf72 haploinsufficiency, accumulation of toxic RNA foci, containing the C9-HRE RNA that disturbs RNA metabolism, and accumulation of the harmful DPR proteins [8,9,53].…”

Section: Discussionmentioning

confidence: 99%

Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage

Huber,

Hietanen,

Heikkinen

et al. 2024

Preprint

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Frontotemporal dementia (FTD) is the second most common cause of dementia in patients under 65 years, characterized by diverse clinical symptoms, neuropathologies, and genetic background. Synaptic dysfunction is suggested to play a major role in FTD pathogenesis. Disturbances in the synaptic function can also be associated with the C9orf72 repeat expansion (C9-HRE), the most common genetic mutation causing FTD. C9-HRE leads to distinct pathological hallmarks, such as C9orf72 haploinsufficiency and development of toxic RNA foci and dipeptide repeat proteins (DPRs). FTD patient brains, including those carrying the C9-HRE, are also characterized by neuropathologies involving accumulation of TDP-43 and p62/SQSTM1 proteins. This study utilized induced pluripotent stem cell (iPSC)-derived cortical neurons from C9-HRE-carrying or sporadic FTD patients and healthy control individuals. We report that the iPSC neurons derived from C9-HRE carriers developed typical C9-HRE-associated hallmarks, including RNA foci and DPR accumulation. All FTD neurons demonstrated increased TDP-43 nucleus-to-cytosolic shuttling and p62/SQSTM1 accumulation, and changes in nuclear size and morphology. In addition, the FTD neurons displayed reduced number and altered morphologies of dendritic spines and significantly altered synaptic function indicated by a decreased response to stimulation with GABA. These structural and functional synaptic disturbances were accompanied by upregulated gene expression in the FTD neurons related to synaptic function, including synaptic signaling, glutamatergic transmission, and pre- and postsynaptic membrane, as compared to control neurons. Pathways involved in DNA repair were significantly downregulated in FTD neurons. Only one gene, NUPR2, potentially involved in DNA damage response, was differentially expressed between the sporadic and C9-HRE-carrying FTD neurons. Our results show that the iPSC neurons from FTD patients recapitulate pathological changes of the FTD brain and strongly support the hypothesis of synaptic dysfunction as a crucial contributor to disease pathogenesis in FTD.

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Section: Discussionmentioning

confidence: 99%

Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage

Huber,

Hietanen,

Heikkinen

et al. 2024

Preprint

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“…This phenotype has now been identified as the most common genetic cause of both familial and sporadic ALS. The exact mechanism by which C9orf72 mutations contributes to ALS is still unknown, but it is hypothesized that these expansions may lead to toxic RNA aggregates and a change in RNA functioning …”

Section: Pathogenic Mechanisms In Alsmentioning

confidence: 99%

“…The exact mechanism by which C9orf72 mutations contributes to ALS is still unknown, but it is hypothesized that these expansions may lead to toxic RNA aggregates and a change in RNA functioning. 13 Since the discovery of C9orf72 mutations, a few studies have identified their prevalence across both fALS and sALS. In a sample of white Europeans and Americans, C9orf72 mutations were prevalent in 39% of fALS and 7% of sALS cases.…”

Section: Pathogenic Mechanisms In Alsmentioning

confidence: 99%

Purinergic P2X₇ Receptor: A Therapeutic Target in Amyotrophic Lateral Sclerosis

McKenzie

Garrett

Werry

et al. 2022

ACS Chem. Neurosci.

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by upper and lower motor neuron loss. The pathomechanisms of ALS are still poorly understood with current hypotheses involving genetic mutations, excitotoxicity, and reactive oxygen species formation. In the absence of a disease-altering clinically approved therapeutic, there is an ever-increasing need to identify new targets to develop drugs that delay disease onset and/or progression. The purinergic P2X7 receptor (P2X7R) has been implicated widely across the ALS realm, providing a potential therapeutic strategy. This review summarizes the current understanding of ALS, the P2X7R and its role in ALS, the current landscape of P2X7R antagonists, and the in vivo potential of these antagonists in preclinical ALS models.

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“…The exact way by which the pathological length C9orf72 repeat expansions drives neurodegeneration is still debated, but three pathomechanisms are being suggested, including loss of physiological functions and gain of toxicity by RNA foci and DPRs, both derived by repeatcontaining RNAs. 159 Directly affecting the production of ribonucleoprotein toxic species, the first in vivo study employing ASOs directed against repeat-enriched RNAs, showed their ability to mitigate RNA foci and DPR burden, with a corresponding improvement of phenotypical signatures. 160 From these encouraging results, a phase 1 trial (NCT03626012, NCT04288856) started enrolling C9orf72 repeat expansion carrying ALS patients, to assess BIIB078, an ASO specifically designed to reduce only the repeat-containing C9orf72 transcripts.…”

Section: Targeting the C9orf72 Expansionmentioning

confidence: 99%

Section: Tdp-43 Targeting Strategiesmentioning

confidence: 99%

Experimental Disease-Modifying Agents for Frontotemporal Lobar Degeneration

Giunta¹,

Solje²,

Gardoni³

et al. 2021

JEP

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Frontotemporal dementia is a clinically, genetically and pathologically heterogeneous neurodegenerative disorder, enclosing a wide range of different pathological entities, associated with the accumulation of proteins such as tau and TPD-43. Characterized by a high hereditability, mutations in three main genes, MAPT, GRN and C9orf72, can drive the neurodegenerative process. The connection between different genes and proteinopathies through specific mechanisms has shed light on the pathophysiology of the disease, leading to the identification of potential pharmacological targets. New experimental strategies are emerging, in both preclinical and clinical settings, which focus on small molecules rather than gene therapy. In this review, we provide an insight into the aberrant mechanisms leading to FTLD-related proteinopathies and discuss recent therapies with the potential to ameliorate neurodegeneration and disease progression.

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Insights into disease mechanisms and potential therapeutics for C9orf72-related amyotrophic lateral sclerosis/frontotemporal dementia

Cited by 7 publications

References 274 publications

Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage

Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage

Purinergic P2X₇ Receptor: A Therapeutic Target in Amyotrophic Lateral Sclerosis

Experimental Disease-Modifying Agents for Frontotemporal Lobar Degeneration

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Insights into disease mechanisms and potential therapeutics for C9orf72-related amyotrophic lateral sclerosis/frontotemporal dementia

Cited by 7 publications

References 274 publications

Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage

Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage

Purinergic P2X7 Receptor: A Therapeutic Target in Amyotrophic Lateral Sclerosis

Experimental Disease-Modifying Agents for Frontotemporal Lobar Degeneration

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Product

Resources

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Purinergic P2X₇ Receptor: A Therapeutic Target in Amyotrophic Lateral Sclerosis