Cell Death Mechanisms

This group investigates the mechanisms of neuronal cell death in the retina to forward the development of novel therapies for retinal diseases.

Neurodegenerative diseases are an ever-increasing health concern in the ageing human populations. The retina as an integral part of the central nervous system (CNS) combines easy access with a large number of animal models available for investigations of development, function, and pathology. We use the retina as a model system to investigate neuronal degeneration with a particular focus on photoreceptor cell death and inherited retinal degeneration (RD), diseases grouped under several different clinical terms including Retinitis Pigmentosa (RP), Leber´s Congenital Amaurosis (LCA), and Achromatopsia (ACHM).

Contrary to common belief neurodegenerative diseases can be caused by a large variety of different mechanisms (Figure 1). Therefore, for a successful treatment development it is important to first understand what mechanism(s) is (are) responsible for a given disease phenotype.

Figure 1: Comparison of different cell death mechanisms. Shown are mechanistic diagrams illustrating the cellular processes executed during apoptosis, necroptosis, PARthanatos, and cGMP-dependent cell death in the retina.

Yellow highlight indicates signalling molecules/processes; orange highlight indicates complex processes likely involving multiple proteins and molecules. Figure modified after Power et al., 2019.

Classical apoptosis involves an intracellular signal (intr. sign.) generated expression of pro-apoptotic genes and proteins and the translocation of BCL2 family proteins to produce mitochondrial outer membrane permeabilization (MOMP). The resulting leakage of cytochrome c (cyto. c) from the mitochondria to the cytoplasm leads to its combination with apoptotic protease activating factor-1 (APAF1) and caspase-9 to activate executioner caspases, such as caspase-3 and -7.

Necroptosis is triggered by extracellular signals (extr. sign.) leading to activation of tumour necrosis factor receptor-1 (TNFR1), which when associated with its adaptor protein TRADD drives the activation of receptor interacting protein kinase-1 (RIPK1). RIPK1 activates RIPK3 and then mixed-lineage-kinase-domain-like pseudokinase (MLKL) resulting in the extracellular release of highly immunogenic damage-associated molecular patterns (DAMPs) and the production of a strong inflammatory response.

In PARthanatos genomic or metabolic stress and resultant DNA damage causes over-activation of poly ADP-ribose polymerase (PARP). PARP will produce poly-ADP-ribose (PAR) polymers and deplete cellular energy resources in the process. PAR polymers can apoptosis inducing factor (AIF) leading to DNA degradation, while energy depletion will induce increased levels of intracellular Ca²⁺ and activation of calpain-type proteases.

In cGMP-dependent photoreceptor cell death a mutation-induced up-regulation of cGMP on the one hand causes activation of cyclic-nucleotide-gated-channel (CNGC), leading to Ca²⁺ influx and calpain activation. On the other hand, cGMP-dependent activation of protein kinase G (PKG) is somehow (perhaps involving the phosphorylation of the PKG substrate VASP) associated with histone deacetylase (HDAC) and PARP activation. Importantly, cGMP-dependent photoreceptor cell death offers new targets for photoreceptor neuroprotection.

RD affects predominantly photoreceptors and in the developed world it is the prevalent cause of blindness in the working age population. Although the underlying genetic mutations have been identified in many cases, the degeneration mechanisms are still unknown, and the disease is usually untreatable. A large variety of different cell death mechanisms have been studied in the past 10-15 years (Figure 1), now it is important to identify and detail the processes causing RD. A precise knowledge of these mechanisms at play is essential for the development of rational therapies. The hope is that once we understand the mechanisms underlying retinal degeneration, we will be able to use this knowledge to develop treatments for RP and related diseases that affect photoreceptors.