Cell cycle S phase markers are expressed in cerebral neuron nuclei of cats infected by the Feline Panleukopenia Virus

Abstract

The cell cycle-associated neuronal death hypothesis, which has been proposed as a common mechanism for most neurodegenerative diseases, is notably supported by evidencing cell cycle effectors in neurons. However, in naturally occurring nervous system diseases, these markers are not expressed in neuron nuclei but in cytoplasmic compartments. In other respects, the Feline Panleukopenia Virus (FPV) is able to complete its cycle in mature brain neurons in the feline species. As a parvovirus, the FPV is strictly dependent on its host cell reaching the cell cycle S phase to start its multiplication. In this retrospective study on the whole brain of 12 cats with naturally-occurring, FPV-associated cerebellar atrophy, VP2 capsid protein expression was detected by immunostaining not only in some brain neuronal nuclei but also in neuronal cytoplasm in 2 cats, suggesting that viral mRNA translation was still occurring. In these cats, double immunostainings demonstrated the expression of cell cycle S phase markers cyclin A, cdk2 and PCNA in neuronal nuclei. Parvoviruses are able to maintain their host cells in S phase by triggering the DNA damage response. S139 phospho H2A1, a key player in the cell cycle arrest, was detected in some neuronal nuclei, supporting that infected neurons were also blocked into the S phase. PCR studies did not support a co-infection with an adeno or herpes virus. ERK1/2 nuclear accumulation was observed in some neurons suggesting that the ERK signaling pathway might be involved as a mechanism driving these neurons far into the cell cycle.

Neuronal Vacuolization in Feline Panleukopenia Virus Infection

“…5 Recent reports show that feline parvoviruses are able to maintain their host cells in the S phase by a proposed ERK signaling pathway, as an ERK1/2 nuclear accumulation was observed, as well as the intranuclear occurrence of the key cell cycle arrest player S139 phospho-H2A1, in parvovirus-infected neurons. 9 FPV infection with mild lymphohistiocytic inflammation of the meninges and cerebellum was described in a 2-week-old cat, which exhibited parvoviral antigen in neurons of the granular layer of the cerebellum and in the gray matter of the spinal cord, as well as in most other brain regions, in macrophages, microglia, astrocytes, and ependymal cells. 13 Similarly, FPV antigen was detected in glial cells and neurons of 4 cats showing focal neuronal satellitosis and neuronophagia, especially of the interthalamic adhesion.…”

A Lipidated Peptide with Mitochondrial Membrane Localization in Human A549 Lung Cells: From Enhanced Cell-Penetrating Properties to Biological Activity Mechanism

“…The proliferating cell nuclear antigen (PCNA) is a key factor in the S phase, which depends on the expression of cyclin A1 and cyclin-dependent kinase (CDK 2) (see Figure ). In addition, it is related to the activity of p21 . Both down-regulation of the cell cycle regulatory complex (cyclin A1/CDK 2/PCNA) and up-regulation of p21 expression contribute to S-phase arrest.…”

Evidence of cell cycle re-entry in post-mitotic, terminally differentiated feline neurons

“…Thus, S-phase-related DNA polymerase, which is required for the synthesis of essential double-stranded intermediates prior to parvovirus transcription and translation (Berns 1990 ), should not be active in mature neurons. However, contrary to the hypothesis of permanent G0-restriction of mature neurons (Nagy 2000 ; Zhang et al 2020 ), there is evidence of parvovirus-antigen and viral mRNA translation and replication in mature neurons of cats (Garigliany et al 2016 ; Url et al 2003 ), as well as the expression of S-phase proteins in neurons of cats with naturally occurring panleukopenia (Poncelet et al 2016 ).…”