Aging is an important risk factor for neurodegenerative disorders (neurodegenerative disorders), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD ).
Protein synthesis has historically been described as decreasing with age, although not all studies agree and often point to high organ and tissue variability. Protein degradation is also commonly described as compromised in aging
Analysis of brain protein levels in the physiologically aged brain, however, showed only minor changes in protein abundance in the older adult brain compared to the young adult brain. However, a recent theory indicates that the alterations observed in neurodegenerative disorders could be linked to the minimization of proteomic costs, reflecting a new prioritization of bioenergetic costs, which would preserve the most "expensive" proteins in energy from the aged brain while replacing more easily metabolically less expensive proteins.
To test this theory, it is interesting to study protein turnover, which regulates the balance between protein synthesis and degradation, because it could be particularly affected by aging and could lead to changes prelude to neuropathology. The turnover of proteins begins with their destruction, the catabolism of proteins is a key function of the digestive process. The amino acids resulting from these proteins thus degraded can be transformed into fuel for the Krebs cycle/citric acid (TCA).
Researchers led by Anja Schneider of the German Center for Neurodegenerative Diseases in Bonn and Eugenio Fornasiero of the University Medical Center Göttingen, both in Germany, measured the half-lives of more than 3,500 proteins in mouse brain. They found an average increase of 20 percent with age.
For Alzheimer's disease, these life-extending proteins included:
- the group of Tau proteins (MAPT)
- ADAM10 which is correlated with the appearance of different types of synaptopathies, ranging from neurodevelopmental disorders, i.e. autism spectrum disorders, to neurodegenerative diseases, i.e. Alzheimer's disease.
- DBN1 A decrease in the amount of this protein in the brain has been implicated as a possible contributing factor in the pathogenesis of memory impairment in Alzheimer's disease.
- CTSDs which are implicated in the pathogenesis of several diseases, including breast cancer and possibly Alzheimer's disease.
For Parkinson's disease, they included:
Alpha-synuclein, a protein which in humans is encoded by the SNCA gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and the subsequent release of neurotransmitters. It is abundant in the brain, while smaller amounts are found in the heart, muscle, and other tissues. In the brain, alpha-synuclein is found primarily in the axon terminals of presynaptic neurons.
Alpha-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. These disorders are known as synucleinopathies.
PARK7, Under oxidative conditions, the deglycase protein DJ-1 inhibits the aggregation of α-synuclein via its chaperone activity, thus functioning as a redox-sensitive chaperone and as an oxidative stress sensor. The functional protein DJ-1 has been shown to bind to metals and protect against metal-induced cytotoxicity of copper and mercury. Defects in this gene cause early-onset autosomal recessive Parkinson's disease
For ALS, they included:
TUBA4A, The alpha-4A chain of tubulin is a protein which in humans is encoded by the TUBA4A gene. This gene has only rarely been associated with ALS. Overall, ALS-related genes can be categorized into four groups based on the cellular pathways in which they are involved: (1) protein homeostasis; (2) homeostasis and RNA trafficking; (3) cytoskeletal dynamics; and (4) mitochondrial function.
The reason TUBA4A might be associated with ALS is that motor neurons and skeletal muscle cells are known to be the largest cells in the human body. The significant length of these cells makes them highly dependent on the correct architecture of the cytoskeleton, the integrity of which is essential for the axonal transport necessary to maintain the integrity of synapses. Several mutations in the tubulin beta-4A (TUBA4A) gene destabilize microtubules by impairing repolymerization, likely contributing to axonal degeneration in MN.
SOD1, whose protective role against oxidative stress has been well studied, but whose mutations were previously only associated with 25% cases of familial ALS.
Conclusion The authors of this article observed a previously unknown alteration in proteostasis that is correlated with parsimonious protein turnover with high biosynthetic costs, revealing a global metabolic adaptation that preludes neurodegeneration.
However, nothing in this study explains how malformed, poorly localized proteins might appear. This study only shows a correlation between the half-life of proteins and certain neurodegenerative diseases.
Their results suggest that future therapeutic paradigms, aimed at addressing these metabolic adaptations, may be able to delay the onset of neurodegenerative disorders.
Among these we could mention certain factors related to metabolism which determine the half-life of proteins such as pH and temperature. It is well known that aging cells have an increasing pH: They become basic. when the daughter cells come from an aging mother cell, the daughter's age is "reset". A parent cell becomes less acidic as the parent cell ages. Daughter cells, on the other hand, have very acidic vacuoles.