Neuronal degeneration is mostly caused by the accumulation of dangerous deposits – often clumped-together proteins – and damages to the functional units within the cells, so called organelles (mitochondria, endoplasmic reticulum, lysosomes) of long-living neurons. These developments lead to slow, progressive damage and eventually death of specific groups of neurons in the brain. Based on this knowledge, scientists now aim to identify very early events in the development of neurodegeneration that can be inhibited before the damage accumulates and causes a massive loss of neurons. Obviously, this is a tricky situation, as therapies – to be successful – may have to start ten to twenty years before the first symptoms appear, at the time when deposits first start accumulating in neurons. Currently, we lack non-invasive diagnostic tools to detect this stage, for example by mass screening the whole population. Once neurons have started dying, there is much less chance to stop the domino effect of disease. For example, approximately 80% of dopaminergic neurons (neurons that synthesize the neurotransmitter dopamine, which is required for the healthy functioning of the nervous system) begin to atrophy before first clinical symptoms of Parkinson’s disease appear, indicating that there is a long therapeutic time window. Similarly, in Alzheimer’s disease, damage within hippocampal neurons, which are critical for memory connections, often accumulates for many years before the nerve cells lose their functions.
So far, none of the aforementioned neurodegenerative diseases is curable and treatment has only dealt with the late stage symptoms, delaying progression of the disease at best. Multiple reasons exist for this. First, we have to consider the incredible complexity of the human brain. It has about 86 billion neurons, each having about 7000 synaptic connections to other neurons. Secondly, the non-dividing, long-lived nature of neurons make them prone to accumulation of damage during their lifetime. Thirdly, the brain is a secluded organ, difficult to approach for diagnostics or to administer conventional drugs. Altogether, targeting neurodegenerative diseases is one the greatest challenges in biomedicine today.
Until now, most drug development for neuronal degeneration focused on using chemical compounds, antibodies, nucleic acids or proteins able to prevent and possibly reverse the build-up of the proteins that can cause the disease, such as synuclein for Parkinson’s and amyloids for Alzheimer’s. However, all attempts to target aggregation-prone proteins through above-mentioned therapies have so far fallen short of expectations. More recently, attention has been focused on the cells’ own quality control systems, which are responsible for removing any dangerous deposits or damaged organelles. Defects in those cellular control systems may contribute to or even cause neurodegeneration. At the same time, boosting the performance of those internal mechanisms may have a protective effect. One of those is autophagy, which enables cells to remove damaged or dangerous material from our body. Novel innovative approaches try to flag dangerous components and target the autophagic waste machinery for their removal.