A newly discovered genetic condition caused by faulty protein synthesis which causes delayed development and learning difficulties could be treated by a compound originally isolated from human sperm, say scientists.
The University of Manchester researchers, with collaborators from the UK, France and US, identified rare changes in a gene called EIF5A in 7 Children with delayed development and learning difficulties from, hospital in the UK, France and the USA.
Their study, published today in Nature Communications, used yeast cells and zebrafish, to show the disease could be potentially treated with a nutritional supplement called spermidine.
The supplement is relatively safe and has been shown to have potential benefit in several other human conditions and is found in foods like old cheese, mushrooms, soy products, legumes, corn and whole grains.
The condition, which is yet to be named, may affect one between one in a thousand or one a million people – the precise number is not known.
Dr Siddharth Banka, Clinical Senior Lecturer at The University of Manchester, who led the study said: “This is an important finding that gives an accurate diagnosis for the first time to these patients, as well as a potential treatment in time.
“We don’t know how many people suffer from this new and unnamed condition, but we do feel there are more patients in the UK and around the world waiting to be diagnosed.”
The study also shows the human brain depends on proteins that are difficult for cells to synthesize.
Proteins are made in cells with the help of tiny machines, called ribosomes which link together different series of 20 different kinds of building blocks called ‘amino acids’.
Amino acids can be arranged into millions of possible combinations to make all the varied proteins our bodies need for a healthy life.
Some amino acid combinations are trickier for ribosomes to join together. Understanding how cells manage to efficiently produce such a wide variety of proteins is an important question for science.
EIF5A is known to help ribosomes make tricky proteins and without it they can’t be synthesised in the brain.
Dr Victor Faundes, PhD student at The University of Manchester who was responsible for the discovery, said: “We were intrigued by this finding and wanted to understand how changes in this gene are causing this disease. We thought that if we could identify the mechanism of the disease, perhaps we can develop a treatment for our patients.”
Drs Banka and Faundes along with the University of Manchester colleagues, Prof Graham Pavitt and Dr Paul Kasher showed that the EIF5A genetic changes reduces the ability of ribosomes to make enough tricky proteins.
And that impacted how cells grow in a petri dish, as well as head development in zebrafish.
Prof Pavitt, who studies the biological basis of protein production in cells, said: “Imagine a car with faulty suspension. Although the car can work well on smooth straight roads, it has to slow down on uneven surfaces. Similarly, a ribosome without functioning eIF5A has a slow and bumpy journey to make some tricky proteins.”
Dr Kasher, who studies zebrafish for understanding and treating human diseases, said: “Being able to identify a potential treatment for a genetic condition at this early stage of discovery is rare.”
But he added: “More patients need to be identified and much more research needs to be done before patients can be treated.”
Dr Banka added: “Our work illustrates how useful it is for scientists with different expertise to collaborate. This finding opens new avenues to understand the function of EIF5A in humans and hopefully one day we will be able to treat these patients.”
he inevitable biological process of aging is a primary driver of various diseases, such as cardiovascular diseases, cancer, and neurodegenerative diseases. Neurodegenerative diseases, especially Parkinson’s disease (PD) and Alzheimer’s disease (AD), exhibit typical age-dependent characteristics, such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion and altered intercellular communication [1–3].
This point suggests that the factors accelerating aging are also involved in the development of neurodegenerative diseases. Werner syndrome (WS), is a disease characterized by an accelerated aging process. As a classical premature aging disease, etiological exploration of WS can shed light on the mechanisms of normal human aging and facilitate the development of interventional strategies to improve healthspan [4].
Spermidine can ameliorate the damage as a result of oxidative stress in aged mice as well as promotes autophagy via chromatin acetylation. It has been shown to exhibit cross-species anti-aging effects, covering yeast, nematodes, fruit flies, and human cells [5].
Spermidine prolongs lifespan in nematodes, fruit flies, and mice, and suppresses age-induced memory impairment (AMI) in aging fruit flies [6, 7]. The aforementioned benefits of spermidine may be contributed by different mechanisms, but at least spermidine-induced autophagy plays a key role since many of the benefits were dependent on different autophagy pathways [8].
It has been reported that in the Drosophila model of PD, spermidine feeding can inhibit the early mortality of human α-synuclein protein heterologous expression. Similarly, administration of spermidine can rescue loss of dopaminergic neurons in PD nematodes expressing α-synuclein and reduce PD-related neurodegeneration, which coincided with induction of autophagy [9].
Mitochondria participate in multiple metabolic pathways (such as oxidative phosphorylation and the tricarboxylic acid cycle), and play a major role in energy production required for normal cell activity [10]. Mitochondrial dysfunction leads to the accumulation of reactive oxygen species (ROS) impairs ATP production and the cell signaling pathways from and to mitochondria, makes neurons susceptible to endogenous and exogenous stress-induced death, thereby accelerating aging and the progression of AD, PD, among others [11–15].
Mitophagy is a sub-type of macro-autophagy that removes damaged or superfluous mitochondria, thereby maintaining mitochondria homeostasis. The PINK1 / PDR-1 pathway is an important mitophagy regulatory pathway in nematodes, while in mammals is PINK1 / Parkin.
Under normal circumstances, Parkin is located in the cytoplasm and its E3 ubiquitin ligase activity is inhibited. At physiological condition, PINK1 is transported into the mitochondrial intermembrane space where MPP and PARL cleave the mitochondrial targeting sequence and trans-membrane domain of PINK-1; furthermore, cleaved PINK-1 is degraded by the ubiquitin-proteasome system [16, 17].
Upon mitochondrial damage, an alteration in mitochondrial membrane potential (MMP) prevents the translocation of PINK1, which facilitates anchoring of PINK1 on the outer mitochondrial membrane. Subsequent auto-phosphorylation of PINK1 leads to its activation and translocation of cytosolic Parkin to the mitochondrial membrane. PINK1 in turn, phosphorylates and activates Parkin, an E3 ubiquitin ligase, which conjugates ubiquitin onto various OMM proteins, such as voltage dependent anion channel (VDAC) [18, 19].
Although extensive mechanistic studies of the PINK1 / Parkin (PDR-1) pathway have been performed, the role of PINK1 / Parkin (PDR-1)-dependent mitophagy in vivo remains unclear. Multiple studies have found that mitochondrial dysfunction is associated with aging and neurodegenerative diseases [15, 20]. Studies have shown that mitophagy defects appear in postmortem brain tissues of human and mice based on tau and Aβ AD models, as well as in AD patients [21, 22].
Enhancing mitophagy can eliminate AD-related hyperphosphorylation of tau protein in human neuronal cells and reverse memory deficits in the transgenic tau nematodes and mice [21]. Also in PD, studies have found that PD pluripotent stem cell (iPSC) -derived neuronal cells, PD animal models, and brain tissue samples from patients with PD are characterized by mitochondrial dysfunction and its associated oxidative stress and inflammatory response [23–26].
In a series of WRN-deficient cells and WS model nematodes, impaired mitochondrial function and mitophagy were found to mediate accelerated aging of WS. After nicotinamide adenine dinucleotide (NAD+) precursor supplementation, mitochondrial function was improved and WS symptoms were improved [27].
In summary, mitochondrial damage is likely to be a common phenomenon underlying many neurodegenerative diseases. As the research on the causality of mitophagy defects in AD, PD and other neurodegenerative diseases continues to progress, it will provide new ideas for the development of drugs inducing mitophagy and promoting the clearance of damaged mitochondria as a strategic therapeutic target.
Dietary spermidine exerts cardioprotective effects through enhanced autophagy, reduces cardiac hypertrophy, improves diastolic function, and can extend mouse lifespan [28]. In addition to autophagy, spermidine also enhances mitophagy in cultured cell lines, including human fibroblasts and cardiomyocytes [28].
Spermidine induces mitophagy mainly by inhibiting mTOR and activating phosphorylation of 5′adenosine monophosphate-activated protein kinase (AMPK) [8, 29], which antagonizes mTORC1 at the functional level and may further facilitate autophagic. In addition, ataxia-telangiectasia mutated protein kinase (ATM)-dependent putative kinase 1 (PINK1)/ Parkin signaling can also be activated by spermidine [30]. However, additional mechanisms between spermidine and mitophagy remain elusive.
Here, we expand spermidine’s scope of potential protective effects during the neurodegenerative diseases and premature aging disease in age-related diseases with WS, PD, and AD disease model nematodes, and investigate the possible underlying mechanisms.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521492/
Original Research: Open access.
“Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine” by Víctor Faundes, Martin D. Jennings, Siobhan Crilly, Sarah Legraie, Sarah E. Withers, Sara Cuvertino, Sally J. Davies, Andrew G. L. Douglas, Andrew E. Fry, Victoria Harrison, Jeanne Amiel, Daphné Lehalle, William G. Newman, Patricia Newkirk, Judith Ranells, Miranda Splitt, Laura A. Cross, Carol J. Saunders, Bonnie R. Sullivan, Jorge L. Granadillo, Christopher T. Gordon, Paul R. Kasher, Graham D. Pavitt & Siddharth Banka. Nature Communications
