Research Group Leader - CECAD Research Center
A pathological hallmark of many age-associated neurodegenerative diseases is the presence of misfolded protein aggregates, indicating disturbances in proteostasis. Protein aggregates in the cell are cleared by autophagy, a cellular pathway known to be impaired in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. However the precise mechanism, which leads to autophagosomal malfunction in neurons and its relationship to protein aggregations and neuronal death remains unresolved. It is currently not known whether the increase in autophagosomes observed in the degenerating neurons plays a protective role or instead contributes to the pathology of the neurodegeneration.
Our research: Autophagy is a cellular degradation pathway, triggered by stress conditions, such as nutrient starvation, which is involved in the turnover of proteins and organelles through lysosomal degradation. Although all cell types have autophagy pathway, growing number of evidence suggests that the mechanisms underlying autophagy in neurons might differ from non-neuronal cells. Studies using GFP-LC3 (an autophagosomal marker) transgenic mice, as well electron microscopic observations indicate that the autophagosomes are relatively scarce in healthy neurons. Two possibilities can explain the scarcity of neuronal autophagosomes. One possibility is that the autophagic activity is maintained at a very low level in the brain. Indeed, the brain is well protected against systemic starvation. Transport of glucose and amino acids across the blood-brain-barrier, as well as the release for trophic factors from supporting glia cells ensures the supply of metabolites under normal and/or energy restricted conditions. Therefore, active autophagy in neurons may not be necessary to maintain the cellular energy needs. The other possibility is that due to the highly efficient autophagosomal degradation, autophagosomes only transiently exist in healthy neurons and cannot be observed at a detectable level. High efficiency of autophagic degradation in neurons is supported by the fact that the inhibition of lysosomal degradation causes rapid accumulation of autophagosomes in neurons under nutrient rich conditions (Fig. 1). If autophagic activity is highly maintained in normal healthy neurons, what is the primary role of basal autophagy in neurons?
Dr. Natalia Kononenko and her group investigate the molecular and cellular processes underlying autophagy induction in neurons. The key research questions in Natalia Kononenko’s labs are:
Our successes: Dr. Natalia Kononenko and her co-workers have contributed to the understanding of the molecular and cell biological regulation of autophagosomal trafficking in neurons. The group has identified endocytic adaptor protein complex-2 (AP-2), as a novel adaptor for autophagosomal trafficking in neurons. AP-2 deficient neurons accumulate immobile multi-lamellar autophagosomal structures (Figs.2, 3) and reveal severe defects in dendrite maintenance (Fig. 4).
Our goals: Increased induction of autophagy is relatively frequent in neurodegenerative diseases. While increased autophagy has been shown to facilitate the clearance of aggregation-prone proteins and promote neuronal survival, growing evidence indicate that too much autophagic activity can be detrimental and lead to neuronal death. The long-term goal of Dr. Kononenko’s lab is to understand the role of autophagy in the pathology of neurodegenerative diseases. To reveal the role of autophagy in the brain areas selectively vulnerable to neurodegeneration (such as entorhinal cortex, striatum and substantia nigra), the group of Dr. Natalia Kononenko aims to develop mouse models for monitoring autophagic turnover rates in the brain in vivo. Given the therapeutic potential of autophagy modulation in neurodegenerative disease, the research performed by Dr. Kononenko’s group may provide new therapeutic targets for treatment of age-associated neurodegenerative disorders.
Our methods/techniques: Research in Dr. Kononenko’s laboratory is performed using live imaging, molecular, genetic and cell biology approaches, as well as state-of-the-art superresolution microscopy and in vivo neuroanatomy techniques (including track-tracing techniques and 3D neuronal reconstructions).
Figure 1: Autophagosomal structures accumulate in the control neurons upon inhibition of lysosomal degradation via application of vATPase blocker Folimycin. Autophagosmal intermediates are visualised via immunostaining with autophagosomal marker LC3b. Late endosomes are visualized with Rab7 positive antibody.