Dysfunction of cerebellar microglia in Ataxia‐telangiectasia

Abstract

Ataxia-telangiectasia (A-T) is a multisystem autosomal recessive disease caused by mutations in the ATM gene and characterized by cerebellar atrophy, progressive ataxia, immunodeficiency, male and female sterility, radiosensitivity, cancer predisposition, growth retardation, insulin-resistant diabetes, and premature aging. ATM phosphorylates more than 1500 target proteins, which are involved in cell cycle control, DNA repair, apoptosis, modulation of chromatin structure, and other cytoplasmic as well as mitochondrial processes. In our quest to better understand the mechanisms

Persistent DNA damage associated with ATM kinase deficiency promotes microglial dysfunction

“…In the present work, the levels of phagocytosis of both damaged and live neuronal material by ATM KO microglia were 50–100% higher compared to WT cells. These observations are somewhat at odds with the recent data on Atm –/ – cerebellar microglia, which are activated, as adjudged by their morphology and increased motility, but show reduced phagocytosis in comparison with controls ( 13 ). While we cannot explain these differences, the expression of genes involved in phagocytosis was upregulated in cerebellar microglia from individuals with A–T, indicating enhanced phagocytic processes in this disease ( 33 ).…”

“…They exist in a highly immune-vigilant state, and this profile is further exacerbated with ageing ( 86 ). In addition, microglia in the cerebellum are enriched in genes associated with active cell clearance ( 93 ), and cerebellar microglia from Atm –/– mice and individuals with A–T are highly activated as compared to other brain regions ( 13 , 33 ). We therefore propose that persistent DNA damage associated with the loss of ATM might exacerbate the phagocytic abilities of highly reactive cerebellar microglia in vivo , resulting in excessive clearance of neuronal material that may contribute to neurodegeneration in A–T.…”

Development of microglia-targeting adeno-associated viral vectors as tools to study microglial behavior in vivo

“…The microglia targeting profiles of these AAV constructs were assessed in three different brain regions: the cerebral cortex (frontal cortex), striatum, and cerebellum. The striatum was selected to compare our results with a previous report using lentiviral vectors with miR-9.T 13 , while along with the striatum, the frontal cortex and cerebellum were chosen as aberrant microglial function in these brain regions have been associated with various neurodegenerative disorders, such as Alzheimer's disease and cerebellar ataxias [24][25][26] . Generally, the transgene expression pattern of AAV depends on the injection dose and the subsequent incubation period.…”

Leveraging the ATP‐P2X7 receptor signalling axis to alleviate traumatic CNS damage and related complications

“…However, aberrant microglial activation, or chronic microglial activation even at a low level, can result in undesirable generation of proinflammatory mediators that damage healthy neural tissues leading to loss of neurological and cognitive functions, a process termed neuroinflammation. A large volume of evidence supports that microglia‐mediated neuroinflammation is a common and major mediator of a variety of CNS diseases 40–49 . Thus, it is imperative to gain a clear understanding of the mechanisms driving microglial activation and neuroinflammation for the development of therapeutic strategies restoring microglial functions and treating CNS diseases.…”

“…A large volume of evidence supports that microglia‐mediated neuroinflammation is a common and major mediator of a variety of CNS diseases. 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 Thus, it is imperative to gain a clear understanding of the mechanisms driving microglial activation and neuroinflammation for the development of therapeutic strategies restoring microglial functions and treating CNS diseases.…”