DNA Damage Triggers a New Phase in Neurodegeneration

Pessina, Fabio; Gioia, Ubaldo; Brandi, Ornella; Farina, Stefania; Ceccon, Marta; Francia, Sofia; Fagagna, Fabrizio d’Adda di

doi:10.1016/j.tig.2020.09.006

Cited by 49 publications

(34 citation statements)

References 163 publications

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“…Consistent with all defined cytoplasmic and nuclear alterations, dysfunctional PCs in pcd mice ultimately activate the caspase-mediated apoptotic pathway (Figure 4I), in-cluding by upregulating the expression of neuronal apoptosis facilitators such as Bim3 and Bcl2l11 [9,[17][18][19]48,51,52,70]. In summary, some types of nuclear rearrangement and pathological alterations observed in PCs harbouring the pcd mutation resemble the cellular alterations described in certain human neurodegenerative diseases [66,71,72].…”

Section: Degeneration Of Purkinje Cellssupporting

confidence: 77%

The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease

et al. 2021

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Recent reports have identified rare, biallelic damaging variants of the AGTPBP1 gene that cause a novel and documented human disease known as childhood-onset neurodegeneration with cerebellar atrophy (CONDCA), linking loss of function of the AGTPBP1 protein to human neurodegenerative diseases. CONDCA patients exhibit progressive cognitive decline, ataxia, hypotonia or muscle weakness among other clinical features that may be fatal. Loss of AGTPBP1 in humans recapitulates the neurodegenerative course reported in a well-characterised murine animal model harbouring loss-of-function mutations in the AGTPBP1 gene. In particular, in the Purkinje cell degeneration (pcd) mouse model, mutations in AGTPBP1 lead to early cerebellar ataxia, which correlates with the massive loss of cerebellar Purkinje cells. In addition, neurodegeneration in the olfactory bulb, retina, thalamus and spinal cord were also reported. In addition to neurodegeneration, pcd mice show behavioural deficits such as cognitive decline. Here, we provide an overview of what is currently known about the structure and functional role of AGTPBP1 and discuss the various alterations in AGTPBP1 that cause neurodegeneration in the pcd mutant mouse and humans with CONDCA. The sequence of neuropathological events that occur in pcd mice and the mechanisms governing these neurodegenerative processes are also reported. Finally, we describe the therapeutic strategies that were applied in pcd mice and focus on the potential usefulness of pcd mice as a promising model for the development of new therapeutic strategies for clinical trials in humans, which may offer potential beneficial options for patients with AGTPBP1 mutation-related CONDCA.

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Section: Degeneration Of Purkinje Cellssupporting

confidence: 77%

The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease

et al. 2021

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“…Finally, non-coding RNAs (ncRNAs) have been associated with both heterochromatin establishment [ 114 ] and DSB responses (reviewed in [ 115 , 116 , 117 ]), but their roles in the DSB repair of pericentromeric regions remains unexplored. The application of recently-developed tools to investigate the role of ncRNAs in repair, such as antisense oligonucleotides (ASOs) [ 118 , 119 , 120 ] coupled with site-specific DSB systems described in this review, provides new opportunities to explore these responses in heterochromatin.…”

Section: Perspectivesmentioning

confidence: 99%

An Expanding Toolkit for Heterochromatin Repair Studies

Rawal

Butova

Mitra

et al. 2022

Genes

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Pericentromeric heterochromatin is mostly composed of repetitive DNA sequences prone to aberrant recombination. Cells have developed highly specialized mechanisms to enable ‘safe’ homologous recombination (HR) repair while preventing aberrant recombination in this domain. Understanding heterochromatin repair responses is essential to understanding the critical mechanisms responsible for genome integrity and tumor suppression. Here, we review the tools, approaches, and methods currently available to investigate double-strand break (DSB) repair in pericentromeric regions, and also suggest how technologies recently developed for euchromatin repair studies can be adapted to characterize responses in heterochromatin. With this ever-growing toolkit, we are witnessing exciting progress in our understanding of how the ‘dark matter’ of the genome is repaired, greatly improving our understanding of genome stability mechanisms.

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“…Once foci are positioned in close proximity, their fusion can be promoted by the phase separating properties of these structures. Liquid-liquid phase separation (LLPS) is typically established by intrinsically disordered regions (IDRs) of proteins interacting with each other through multivalent weak interactions, which create a local environment with distinct biophysical properties from its surroundings (reviewed in [53] ). At repair sites LLPS appears to be induced by multiple components, including: i) damage-induced long non-coding RNA, which promote the molecular crowding of the largely unstructured DNA repair protein 53BP1 [54,55] ; ii) the nucleic acidmimicking biopolymer poly(ADP-ribose) (PAR), and its associated protein FUS [56][57][58][59] ; iii) repair proteins, like yeast Rad52, bacterial SSB (the homolog of RPA), and human TopBP1 [52,[60][61][62] ; and iv) chromatin [63][64][65] , for which the ability to create droplets in vitro is dependent on the structurally disordered histone tails, chromatin modifications, and chromatin-associated-proteins [63,64,66] .…”

Section: Phase Separationmentioning

confidence: 99%

“…Notably, phase separated environments are characterized by selective permeability. Thus, in addition to facilitating interactions with other repair foci or nuclear structures, phase separation of repair sites can influence repair pathway choice and promote repair progression by increasing the local concentration of certain repair components while excluding others (reviewed in [5,53] ).…”

Section: Phase Separationmentioning

confidence: 99%

Multi - level dynamics of heterochromatin and repair sites undergoing homologous recombination

Merigliano¹,

Chiolo²

2021

Preprint

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Studies across different organisms show that nuclear architecture and dynamics play central roles in different aspects of homologous recombination (HR) repair. Here we review the most recent discoveries in this field, ranging from directed motions mediating relocalization pathways, to global chromatin mobilization, local DNA looping, and changes in repair focus properties associated with clustering and phase separation. We will highlight how these dynamics work in different contexts, including the molecular mechanisms and regulatory pathways involved. We will also discuss how they function in pericentromeric heterochromatin, which presents a unique environment for HR repair given the abundance of repeated DNA sequences prone to aberrant recombination, the 'silent' chromatin state, and the phase separation characterizing this domain.

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DNA Damage Triggers a New Phase in Neurodegeneration

Cited by 49 publications

References 163 publications

The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease

The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease

An Expanding Toolkit for Heterochromatin Repair Studies

Multi - level dynamics of heterochromatin and repair sites undergoing homologous recombination

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