Figure 2.

Schematic representation of the major cellular events mediated by cell-cycle proteins and likely to be underpinning neurodegeneration in the adult olfactory bulb. Adult born neurons in the olfactory bulb (OB) can re-enter the cell cycle (CCE; light green box) following various cellular events (highlighted in yellow boxes). These include DNA damage or aberrant cell cycle control due to loss of function mutations in key cell cycle genes such as Rb, p130, p53, Pten or others. CCE (G1/S phase checkpoint) requires phosphorylation of Rb by Cdk4/Cyclin D1 among others mitogenic events. CCE primarily triggers DNA repair (dark green box) but may be possibly accompanied by inflammatory response of resident microglia and/or non-mitogenic signaling such as neuroplasticity. Neurons with failed DNA repair may proceed to the S-phase and undergo: (1) apoptosis e.g., mediated by E2F1, (2) senescence induced by p53 or p16 (with manifestation of senescence-associated secretory phenotype (SASP) (red boxes) or (3) a mitotic-steady state with accumulation of additional insults that will lead to protein aggregation(s)/pathology (yellow boxes) and neurodegeneration eventually (red box). The early steps of prion-like pathologies e.g., Tau phosphorylation may be triggered by several potential kinases with upregulated activities such as cytoplasmic Cdk5, GSK3β, c-Abl and/or others. Refer to text for references. OE, Olfactory epithelium; GCL, granule cell layer; GL, glomerular layer.