Ribosomal biogenesis as an emerging target of neurodevelopmental pathologies

Hetman, Michał; Słomnicki, Łukasz P.

doi:10.1111/jnc.14576

Cited by 86 publications

(84 citation statements)

References 187 publications

(289 reference statements)

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“…Increasing evidence points to a critical link between dysregulated ribosome biogenesis and neurodevelopmental pathologies, including microcephaly 48 . The clinical features observed in patients mutated in RRP7A, however, differ from the usual findings in patients with mutations in genes associated with ribosome biogenesis.…”

Section: R P 7 a + /+ R R P 7 A -/R R P 7 A + /+ R R P 7 A -/R R P 7 mentioning

confidence: 99%

“…Analyses of human foetal brain sections, zebrafish, cell models, and primary cells from patients show that RRP7A levels and functionality is critical in neocortex development and neurogenesis and provide evidence for defective ribosome biogenesis as well as resorption of the primary cilium as pathophysiological mechanisms. Interestingly, recent studies have shown that microcephaly caused by neural tissue infection of flaviviruses, including Zika virus (ZIKV) as well as Japanese encephalitis, West Nile, and Dengue viruses, in part is associated with localization of virus-encoded proteins to both nucleoli 48,60 and the base of primary cilia 61 in conjunction with dysregulated ribosome biogenesis 48 , aberrant length control of primary cilia, and uncontrolled cell fate determination of NPCs 61,62 . In support of both nucleolar and ciliary functions, co-IP analyses and global interactomics confirmed ZIKV-host interactions to key regulatory components of both the cilium-centrosome axis and nucleoli, including NOL6 61,63 .…”

Section: R P 7 a + /+ R R P 7 A -/R R P 7 A + /+ R R P 7 A -/R R P 7 mentioning

confidence: 99%

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RRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis

et al. 2020

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Primary microcephaly (MCPH) is characterized by reduced brain size and intellectual disability. The exact pathophysiological mechanism underlying MCPH remains to be elucidated, but dysfunction of neuronal progenitors in the developing neocortex plays a major role. We identified a homozygous missense mutation (p.W155C) in Ribosomal RNA Processing 7 Homolog A, RRP7A, segregating with MCPH in a consanguineous family with 10 affected individuals. RRP7A is highly expressed in neural stem cells in developing human forebrain, and targeted mutation of Rrp7a leads to defects in neurogenesis and proliferation in a mouse stem cell model. RRP7A localizes to centrosomes, cilia and nucleoli, and patient-derived fibroblasts display defects in ribosomal RNA processing, primary cilia resorption, and cell cycle progression. Analysis of zebrafish embryos supported that the patient mutation in RRP7A causes reduced brain size, impaired neurogenesis and cell proliferation, and defective ribosomal RNA processing. These findings provide novel insight into human brain development and MCPH.

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Section: R P 7 a + /+ R R P 7 A -/R R P 7 A + /+ R R P 7 A -/R R P 7 mentioning

confidence: 99%

Section: R P 7 a + /+ R R P 7 A -/R R P 7 A + /+ R R P 7 A -/R R P 7 mentioning

confidence: 99%

RRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis

et al. 2020

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“…Though ribosomopathies have consequences throughout the body, some ribosomal subunit mutations are connected specifically to neurological disorders, such as those linked to cases of Autism Spectrum Disorder (ASD) and intellectual disability (ID) (Hetman and Slomnicki, 2019;Choe and Cho, 2020). Defects in ribosome function have also been connected to neurodegenerative diseases such as Alzheimer's disease (AD) (Ding et al, 2005;Hernández-Ortega et al, 2016) and Parkinson's disease (PD) (Taymans et al, 2015), and ribosomal frameshifting is implicated in repeat expansion disorders such as Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS) (Gao et al, 2017).…”

Section: Protein Synthesis Linked To Neurological Diseasementioning

confidence: 99%

Homeostatic Roles of the Proteostasis Network in Dendrites

Lottes

Cox

2020

Front. Cell. Neurosci.

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Cellular protein homeostasis, or proteostasis, is indispensable to the survival and function of all cells. Distinct from other cell types, neurons are long-lived, exhibiting architecturally complex and diverse multipolar projection morphologies that can span great distances. These properties present unique demands on proteostatic machinery to dynamically regulate the neuronal proteome in both space and time. Proteostasis is regulated by a distributed network of cellular processes, the proteostasis network (PN), which ensures precise control of protein synthesis, native conformational folding and maintenance, and protein turnover and degradation, collectively safeguarding proteome integrity both under homeostatic conditions and in the contexts of cellular stress, aging, and disease. Dendrites are equipped with distributed cellular machinery for protein synthesis and turnover, including dendritically trafficked ribosomes, chaperones, and autophagosomes. The PN can be subdivided into an adaptive network of three major functional pathways that synergistically govern protein quality control through the action of (1) protein synthesis machinery; (2) maintenance mechanisms including molecular chaperones involved in protein folding; and (3) degradative pathways (e.g., Ubiquitin-Proteasome System (UPS), endolysosomal pathway, and autophagy. Perturbations in any of the three arms of proteostasis can have dramatic effects on neurons, especially on their dendrites, which require tightly controlled homeostasis for proper development and maintenance. Moreover, the critical importance of the PN as a cell surveillance system against protein dyshomeostasis has been highlighted by extensive work demonstrating that the aggregation and/or failure to clear aggregated proteins figures centrally in many neurological disorders. While these studies demonstrate the relevance of derangements in proteostasis to human neurological disease, here we mainly review recent literature on homeostatic developmental roles the PN machinery plays in the establishment, maintenance, and plasticity of stable and dynamic dendritic arbors. Beyond basic housekeeping functions, we consider roles of PN machinery in protein quality control mechanisms linked to dendritic plasticity (e.g., dendritic spine remodeling during LTP); cell-type specificity; dendritic morphogenesis; and dendritic pruning.

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“…Genes responsible for ensuring the translational capacity of the cell play a prominent role in brain development and function [1][2][3] . This emerging link highlights the necessity to understand the diverse and dynamic molecular cues orchestrating assembly of the translation machinery 4 .…”

Section: Introductionmentioning

confidence: 99%

Nol9 is a Spatial Regulator for the Human ITS2 pre-rRNA Processing Complex

Gordon

Pillon

Stanley

2019

Preprint

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The ribosome plays a universal role in translating the cellular proteome. Defects in the ribosome assembly factor Las1L are associated with congenital lethal motor neuron disease and X-linked intellectual disability disorders, yet its role in processing precursor ribosomal RNA (pre-rRNA) is largely unclear. The Las1L endoribonuclease associates with the Nol9 polynucleotide kinase to form the internal transcribed spacer 2 (ITS2) pre-rRNA processing machinery. Together, Las1L-Nol9 catalyzes RNA cleavage and phosphorylation to mark the ITS2 for degradation. While ITS2 processing is critical for the production of functional ribosomes, the regulation of mammalian Las1L-Nol9 remains obscure. Here we characterize the human Las1L-Nol9 complex and identify critical molecular features that regulate its assembly and spatial organization. We establish that Las1L and Nol9 form a higher-order complex and identify the regions responsible for orchestrating this intricate architecture. Structural analysis by highresolution imaging defines the intricate spatial pattern of Las1L-Nol9 within the nucleolar sub-structure linked with late pre-rRNA processing events. Furthermore, we uncover a Nol9 encoded nucleolar localization sequence that is responsible for nucleolar transport of the assembled LasL-Nol9 complex.Together, these data provide a mechanism for the assembly and nucleolar localization of the human ITS2 pre-rRNA processing complex.

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Ribosomal biogenesis as an emerging target of neurodevelopmental pathologies

Cited by 86 publications

References 187 publications

RRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis

RRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis

Homeostatic Roles of the Proteostasis Network in Dendrites

Nol9 is a Spatial Regulator for the Human ITS2 pre-rRNA Processing Complex

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