Apoptotic cell death regulation in neurons

Abstract

Apoptosis plays a major role in shaping the developing nervous system during embryogenesis as neuronal precursors differentiate to become post‐mitotic neurons. However, once neurons are incorporated into functional circuits and become mature, they greatly restrict their capacity to die via apoptosis, thus allowing the mature nervous system to persist in a healthy and functional state throughout life. This robust restriction of the apoptotic pathway during neuronal differentiation and maturation is defined by multiple unique mechanisms that function to more precisely control and restrict the intrinsic apoptotic pathway. However, while these mechanisms are necessary for neuronal survival, mature neurons are still capable of activating the apoptotic pathway in certain pathological contexts. In this review, we highlight key mechanisms governing the survival of post‐mitotic neurons, while also detailing the physiological and pathological contexts in which neurons are capable of overcoming this high apoptotic threshold.

Prenatal sonographic diagnosis of Dandy‐Walker malformation and type III lissencephaly: A novel association

“…As in our case, it typically demonstrates diffuse neurodegeneration involving cortical plate, brainstem, and spinal cord along with numerous macrophages and microcalcifications without inflammatory lesions . In this pathological context, etiopathogenesis of type III lissencephaly appears to be related to the abnormal activation of the apoptotic machinery in the mature postmitotic neurons, which is normally restricted by neuron‐specific regulatory pathways . This neurodegenerative process resulted not only in the major brain abnormalities and enlargement of the subarachnoid spaces seen in our case, but also in amyoplasia and hypoplasia of the genitalia as the spinal cord and hypothalamic–pituitary–gonadal axis are damaged.…”

Robust autoactivation for apoptosis by BAK but not BAX highlights BAK as an important therapeutic target

“…If signaling by BH3-only proteins is limiting, any BAK that became activated could augment that signal to activate more BAK (and BAX) to push the cell over the threshold of BAK and BAX homodimerization required for pore formation. Notably, BAK is not expressed in differentiated neurons [57][58][59] . Its silence there may have evolved to protect the neuronal system against accidental apoptosis, by removing both BAK's intrinsic pore-forming capacity and the feed-forward nature of autoactivation.…”

The gamma-Protocadherins regulate the survival of GABAergic interneurons during developmentally-regulated cell death

“…Whether developing neurons survive or die is determined by the balance of intracellular signals that suppress or initiate the apoptotic cascade (Hollville et al, 2019;Pfisterer and Khodosevich, 2017).…”

“…Together, these studies indicate that cINs are temporally-restricted to respond to pro-survival or pro-death signals and to regulate the apoptotic cell death machinery accordingly. Soon after, pro-apoptotic factors are likely downregulated to terminate the wave of PCD (Hollville et al, 2019) and to stabilize final cIN populations for circuit maturation.…”