One of the hallmarks of neurodegenerative diseases is the accumulation of protein inclusions and translational deficits might account for altered protein homeostasis with a toxic impact on cell functions and survival. Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar dementia (FTLD) are all neurodegenerative disorders characterized by the specific loss of particular populations of neurons and a complex spectrum of symptoms. In addition, Fragile X syndrome (FXS) and Spinal muscular atrophy (SMA) have also been reported related to abnormal ribosomes. Importantly, to explain variable disease onset and progression, environmental and genetic predisposition by modifier genes needs to be deeply understood. For all of these diseases, there is still no cure.
The human 80S ribosome is composed of a 40S and a 60S subunit. The chief function of the 40S subunit, which contains one strand of 18S ribosomal RNA (rRNA) and 33 distinct RPs, is to bind, unwind and scan mRNAs, whereas the 60S subunit is responsible for peptide bond formation and quality control of nascent peptides and is composed of three strands of rRNA (5S, 5.8S and 28S rRNA) and 47 distinct RPs. Deficits in rRNA synthesis and processing have strong effects on neuronal function and survival, and multiple modalities account for their toxic impact. An imbalance in any of their biosynthetic steps may result in dysfunctional protein synthesis altering cellular homeostasis. It is somehow predictable that deficits in rRNA functions have severe consequences for the cells.
Fig. 1. Overview of the main steps of rRNA synthesis and ribosome biogenesis. (Tuorto, 2019)
Current evidence suggests that rRNA dysfunctions might affect the neurodegenerative process, for example, by highly specific and selective functions within the protein synthesis. It remains unclear whether deficits in either rRNA biosynthesis have a causative role in neurodegenerative diseases and/or modify disease progression. Although these are fundamental questions and further research is needed in this direction, it is equally important to understand to which extent neurons are sensitive to such imbalance and what compensatory mechanisms are adopted to cope with a deficit in transcription and/or processing and maturation of rRNA. rRNA syntheses are strongly regulated by cellular stress signals and environmental changes and could be secondary consequences of the degenerative process. It is tempting to speculate that the specific impact of the gut microbiome and nutrient availability on rRNA synthesis might help to better understand the influence of nutrition on the neurodegenerative process. For example, diminished tryptophan-dependent protein biosynthesis has been reported in AD patients, and tryptophanyl-tRNA synthetase (TrpRS) deficiency results in hippocampal neurodegeneration in mice.
Effective treatments halting disease progression will depend on targeting the pathological mechanisms before the onset of the symptoms. A large effort in the search for effective therapies is directed toward the identification of genetic causes to fix the problem at the origin. Nevertheless, it seems also evident that these are multifactorial diseases and a combination of strategies to alter the course of the disease represents a valid parallel research direction. To this end, it will be crucial to investigate in greater detail at what stages rRNA are dysfunctional, whether these are associated with the altered synthesis of specific proteins and might be due to aberrant or insufficient number of individual ribosomes and/or lack of specialized ribosomes, or due to defective neuronal proteostasis as a consequence of altered translational speed and accuracy.
Neurological diseases have always been the focus of scientists' attention because they are usually difficult to overcome. Recent research has shown that ribosome has great potential to help reveal the truth about neurological diseases. Creative Biolabs has been focusing on ribosomes over years and established a comprehensive technology platform. Our platform is equipped with the latest technologies, advanced equipment, and experienced scientists. Thus we are confident in providing our customers with reliable ribosome-related services including but not limited to:
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