Biallelic mutations in NRROS cause an early onset lethal microgliopathy

Smith, Colin; McColl, Barry W.; Patir, Anirudh; Barrington, Jack; Armishaw, Jeremy; Clarke, Antonia; Eaton, J M; Hobbs, Vivienne; Mansour, Sahar; Nolan, Melinda; Rice, Gillian I.; Rodero, Mathieu P; Seabra, Luis; Uggenti, Carolina; Livingston, John H.; Bridges, Leslie; Jeffrey, I; Crow, Yanick J.

doi:10.1007/s00401-020-02137-7

Cited by 18 publications

(19 citation statements)

References 21 publications

(26 reference statements)

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“…Humans lacking CSF1R similarly lack microglia and display craniofacial, limb, bone, and brain abnormalities, and succumb to an early mortality (Oosterhof et al, 2019). Aberrant development, characterized by neurological decline, impaired motor activity, and premature mortality, similarly occurs in humans with a mutated negative regulator of reactive oxygen species (NRROS) (Smith et al, 2020).…”

Section: Regulation Of Microglial Expansion During Late Embryonic and Early Postnatal Lifementioning

confidence: 99%

Regulation of microglia population dynamics throughout development, health, and disease

Hammond

Manek

Kerr

et al. 2021

Glia

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The dynamic expansions and contractions of the microglia population in the central nervous system (CNS) to achieve homeostasis are likely vital for their function.Microglia respond to injury or disease but also help guide neurodevelopment, modulate neural circuitry throughout life, and direct regeneration. Throughout these processes, microglia density changes, as does the volume of area that each microglia surveys. Given that microglia are responsible for sensing subtle alterations to their

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Section: Regulation Of Microglial Expansion During Late Embryonic and Early Postnatal Lifementioning

confidence: 99%

Regulation of microglia population dynamics throughout development, health, and disease

Hammond

Manek

Kerr

et al. 2021

Glia

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“…Patients present with severe white matter defects and neuropathology (Table 1). Pathologically lipid-filled CD68 + macrophages lacking a homeostatic microglia gene signature were observed throughout the white matter, particularly in perivascular regions (Smith et al, 2020). Together, this suggests that microglial modulation of TGF-β signaling is key to brain development.…”

Section: Lrrc33/nrros and Usp18-related Leukodystrophiesmentioning

confidence: 91%

“…Microgliopathies comprise disorders caused by mutations in genes predominantly expressed by microglia, ultimately leading, either directly or indirectly, to white matter defects (Prinz and Priller, 2014). Leukodystrophies related to bi-allelic loss-of-function mutations in CSF1R, TREM2, TYROBP, LRRC33/NRROS or USP18 can be categorized as primary microgliopathies (Oosterhof et al, 2019;Meuwissen et al, 2016;Schwabenland et al, 2019;Dong et al, 2020;Smith et al, 2020). To date, only CSF1R also demonstrates a dominant form of disease (Rademakers et al, 2011).…”

Section: Primary Microgliopathies: Leukodystrophies With Central Microglial Pathologymentioning

confidence: 99%

“…As conditional deletion of Lrrc33 in mice at 3 weeks of age causes no neurological effects, it is likely that LRRC33 is required for the establishment of the microglial network during development (Wong et al, 2017). So far, nine individuals with bi-allelic loss-of-function mutations in LRRC33 have been described, most of whom died between 2 and 4 years of age (Dong et al, 2020;Smith et al, 2020). Patients present with severe white matter defects and neuropathology (Table 1).…”

Section: Lrrc33/nrros and Usp18-related Leukodystrophiesmentioning

confidence: 99%

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The multicellular interplay of microglia in health and disease: lessons from leukodystrophy

Berdowski

Sanderson

Ham

2021

Disease Models &Amp; Mechanisms

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Microglia are highly dynamic cells crucial for developing and maintaining lifelong brain function and health through their many interactions with essentially all cellular components of the central nervous system. The frequent connection of microglia to leukodystrophies, genetic disorders of the white matter, has highlighted their involvement in the maintenance of white matter integrity. However, the mechanisms that underlie their putative roles in these processes remain largely uncharacterized. Microglia have also been gaining attention as possible therapeutic targets for many neurological conditions, increasing the demand to understand their broad spectrum of functions and the impact of their dysregulation. In this Review, we compare the pathological features of two groups of genetic leukodystrophies: those in which microglial dysfunction holds a central role, termed ‘microgliopathies’, and those in which lysosomal or peroxisomal defects are considered to be the primary driver. The latter are suspected to have notable microglia involvement, as some affected individuals benefit from microglia-replenishing therapy. Based on overlapping pathology, we discuss multiple ways through which aberrant microglia could lead to white matter defects and brain dysfunction. We propose that the study of leukodystrophies, and their extensively multicellular pathology, will benefit from complementing analyses of human patient material with the examination of cellular dynamics in vivo using animal models, such as zebrafish. Together, this will yield important insight into the cell biological mechanisms of microglial impact in the central nervous system, particularly in the development and maintenance of myelin, that will facilitate the development of new, and refinement of existing, therapeutic options for a range of brain diseases.

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“…Somatic mutation specifically in the erythro-myeloid progenitor lineage from which microglia derive can drive late-onset neurodegeneration in mice ( 56 ). More recently, biallelic mutations in NRROS (Negative Regulator Of Reactive Oxygen Species), which is necessary for TGFB-1 signaling in microglia, were found to cause an early onset lethal microgliopathy in humans ( 99 , 100 ) and NRROS-deficient (Nrros-/-) mice show neurodegeneration ( 101 ), defects in motor functions and die before 6 months of age ( 102 ). Together, these data show that microglia-specific alterations can cause neurodegenerative disease, confirming that the well-documented immune response to neurodegeneration may not solely be secondary to injury.…”

Section: Positioning Of the Immune System Within The Cnsmentioning

confidence: 99%

The Immune System's Role in the Consequences of Mild Traumatic Brain Injury (Concussion)

2021

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Mild traumatic brain injury (mild TBI), often referred to as concussion, is the most common form of TBI and affects millions of people each year. A history of mild TBI increases the risk of developing emotional and neurocognitive disorders later in life that can impact on day to day living. These include anxiety and depression, as well as neurodegenerative conditions such as chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD). Actions of brain resident or peripherally recruited immune cells are proposed to be key regulators across these diseases and mood disorders. Here, we will assess the impact of mild TBI on brain and patient health, and evaluate the recent evidence for immune cell involvement in its pathogenesis.

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Biallelic mutations in NRROS cause an early onset lethal microgliopathy

Cited by 18 publications

References 21 publications

Regulation of microglia population dynamics throughout development, health, and disease

Regulation of microglia population dynamics throughout development, health, and disease

The multicellular interplay of microglia in health and disease: lessons from leukodystrophy

The Immune System's Role in the Consequences of Mild Traumatic Brain Injury (Concussion)

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