Neurodegenerative diseases (ND) are very complex disorders. Not only is each one different, displaying unique combinations of symptoms and progressing at varying rates, but the biochemical pathways involved are not fully understood. With over 46 million people worldwide currently living with dementia, and a projected 131 million cases by the year 2050, there is significant urgency to better understand the origin and progression of ND (Arbor et al 2017).
Here are three main challenges that need to be addressed in order to make significant progress in the detection and treatment of ND.
Despite giant leaps in our understanding, it is still unclear precisely how toxic misfolded proteins are controlled during ND progression. In healthy cells, we know that misfolded proteins are either degraded or refolded with the help of chaperone proteins. Factors such as stress, mutations, or even aging – in some cases at least – can throw off this system, allowing proteins to escape quality control and form aggregates. Once aggregated, these proteins are extremely stable and promote further aggregation. Scientists have studied these molecular pathways in model organisms such as yeast, C. elegans, or transgenic mice, but to date, animal models have not been able to recreate the biochemical and behavioral phenotypes seen in humans with ND.
Thinking from a clinical perspective, being able to diagnose ND in earlier stages would not only make patients more amenable to treatment but would also enable scientists to monitor and understand disease progression more clearly. To develop earlier diagnosis tools, we need to identify more reliable and specific biomarkers. Moving forward, a combination of disease marker identification, neuroimaging, and diagnostic testing may uncover more sensitive and specific ND biomarkers, which could ultimately pave the way for personalized treatment.
More effective therapies are required to slow the progression of the neurodegenerative process. Stem cell therapies have shown promise in this regard, though these treatments are not always accessible or effective for all genetic backgrounds. In order to understand the most effective therapeutic targets, scientists must first identify which form(s) of disease-associated proteins are actually responsible for the disease. Phenotypic screening is an appealing method to screen for novel targets and therapeutic molecules for ND. The reason is the fact that many ND share common mechanisms and phenotypes — aberrant protein aggregation, excitotoxicity, mitochondrial dysfunction, etc. (Brown et al 2019). Advances in certain technologies such as robotic microscopy, CRISPR screening, machine-learning methods, and high-throughput screening are helping make the large amount of data generated by the screens more manageable. However, despite our ability to capture more and previously inaccessible data in ND research, this mass accumulation of data has not translated into diagnostic and therapeutic solutions to effectively treat ND (Espay et al 2016). Ultimately, further studies are necessary to understand the complex molecular mechanisms involved in these pathways.
While we’ve made significant strides in our understanding of neurodegenerative diseases, especially in the last decade, there’s still work to be done. Our enhanced ability to capture data characterizing the molecules involved in ND progression will aid the development of novel therapeutic strategies.