Abstract
The protein kinase ATM (ataxia-telangiectasia mutated) activates the cellular response to double strand breaks (DSBs), a highly cytotoxic DNA lesion. ATM is activated by DSBs and in turn phosphorylates key players in numerous damage response pathways. ATM is missing or inactivated in the autosomal recessive disorder ataxia-telangiectasia (A-T), which is characterized by neuronal degeneration, immunodeficiency, genomic instability, radiation sensitivity, and cancer predisposition. The predominant symptom of A-T is a progressive loss of movement coordination due to ongoing degeneration of the cerebellar cortex and peripheral neuropathy. A major deficiency in understanding A-T is the lack of information on the role of ATM in neurons. It is unclear whether the ATM-mediated DSB response operates in these cells similarly to proliferating cells. Furthermore, ATM was reported to be cytoplasmic in neurons and suggested to function in these cells in capacities other than the DNA damage response. Recently we obtained genetic molecular evidence that the neuronal degeneration in A-T does result from defective DNA damage response. We therefore undertook to investigate this response in a model system of human neuron-like cells (NLCs) obtained by neuronal differentiation in culture. ATM was largely nuclear in NLCs, and their ATM-mediated responses to DSBs were similar to those of proliferating cells. Knocking down ATM did not interfere with neuronal differentiation but abolished ATM-mediated damage responses in NLCs. We concluded that nuclear ATM mediates the DSB response in NLCs similarly to in proliferating cells. Attempts to understand the neurodegeneration in A-T should be directed to investigating the DSB response in the nervous system.
Highlights
Ity, radiation sensitivity, and predisposition to lymphoreticular malignancies
Similar to proliferating cells, neuron-like cells (NLCs) are capable of activating a pronounced double strand breaks (DSBs) response that is mediated by nuclear ATM
Characterization of Neuronal Differentiation of LA-N-5 and SHSY5Y—Following treatment with RA (LA-N-5 cells) or sequential exposure to RA and brain-derived neurotrophic factor (BDNF) (SH-SY5Y cells), these cell lines underwent morphological differentiation into NLCs resembling primary neurons, including cell dissociation, dendrite extension, and formation of extensive networks (Fig. 1A). These morphological changes were accompanied by the expression of several neuron-specific markers: neurofilament 200 (NF200), neuron-specific class III -tubulin Tuj1, neuronal polarity markers such as tau, microtubule-associated protein (MAP2) and growth-associated protein 43 (GAP43), the neurotrophic receptor TrkA, the retinoic acid receptor, and the neuropeptide calcitonine
Summary
Ity, radiation sensitivity, and predisposition to lymphoreticular malignancies. Cerebellar ataxia typically appears in infancy and is an early sign of a progressive neurological syndrome that includes choreoathetosis, dystonia, oculomotor apraxia, limitation on facial expressiveness, dysarthria, and difficulty in swallowing that often causes aspirations leading to sinopulmonary infections. ATM functions have been investigated mainly in cultured proliferating cells, in which an important role of the DNA damage response is to activate the cell cycle checkpoints [8, 10]. Several investigators suggested that ATM was cytoplasmic in human and murine neuronal tissues and was functioning in pathways unrelated to the DNA damage response [11,12,13].
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