By William Carter
Thanks to the medical revolutions of the last century, and the assured advance of modern medicine into the next, we now live longer than ever in our species’ history. Yet despite the vast resources pooled into fighting disease, one enduring bastion remains – ageing. Ageing is the gradual physiological decline we all experience in the latter half of our lifetimes. The accumulation of ageing’s symptoms eventually overwhelms both our own body’s mechanisms for repair and any medicine’s ability to impede its progress, resulting in our inevitable demise. Among the most dreadful manifestations of this physiological decay are those that invade the mind. Dementia kills millions every year, of which 60-70% of cases are caused by Alzheimer’s disease.
Over many decades, huge efforts have been made to understand this terrible and complex disease. Despite this, while certain treatments can offer fleeting relief, no cure for Alzheimer’s has been found. In the battle against this disease, a new frontier has opened. Optimism is easily misplaced, but research into a cellular process called autophagy and the ramifications of its dysfunction, is opening up a new world of possibilities. In every cell, a delicate balance must be struck between synthesis and degradation to ensure its healthy functioning. In this battle for homeostasis, autophagy is an incredibly important weapon in our cellular arsenal. The autophagic mechanism gobbles up all the misfolded proteins, malfunctioning organelles, cytotoxic aggregates and more, and disposes of them before they can wreak havoc on our delicate cellular machinery.
The process starts with formation of phagophores; special bilayer membranes that envelop all the nasty proteins and broken organelles. The phagophore seals itself up, forming a secure little pocket called an autophagosome, which then fuses with lysosomes to degrade all the contents with powerful hydrolases. When the mechanisms underlying autophagy are disrupted, cells lose an effective means of housekeeping, leaving dangerous proteins and dysfunctional organelles running riot in the cytoplasm. Without intervention, the accumulation of debris and the damage wrought can result in accelerated ageing of the cell (Tran & Reddy, 2021).
“A cells’ ability to undergo autophagy, which clears damaged proteins and other debris such as bacteria and viruses from your cell, is reduced as we age,” says Dr. Peter Hamley of Samsara Therapeutics, a company at the forefront of autophagy targeted drug discovery. This natural and progressive dysfunction of the autophagy apparatus allows for the degeneration of cellular components and accumulation of harmful protein aggregates in our cells (including Alzheimer’s infamous Aβ). The resulting damage in turn expedites the onset of cellular senescence, and so in the brain, neurodegeneration (Moreira et al., 2010). “Boosting [autophagy] in later life may lead to health benefits and greater longevity – this has been shown in worms, flies and mice,” suggests Hamley. The research at Samsara is using an innovate platform called Lysoseeker™ to identify and screen a whole range of molecules that could act to promote autophagy in our cells.
There are various methods for monitoring the changes in autophagy, Hamley explains: “We can measure the ability of a cell to undergo autophagy simply by starving it of nutrients. In healthy cells autophagy increases, in ones with dysfunctional autophagy it doesn’t.” To assess the efficacy of ‘lead’ molecules, Hamley continues “the most common of which is following the fate of a protein called LC3 which specifically accumulates on the forming membrane of an autophagosome and stays there until it is degraded in the autolysosome. So it goes through the entire process and we can engineer a fluorescent probe to attach to the LC3, allowing us to monitor the process.”
Equipped with these techniques, their unique expertise and the Lysoseeker™ platform, Samsara are leading the way forward, making huge bounds towards substantial and effective interventions for restoring autophagy to our cells. The importance of autophagy in cellular maintenance is only becoming more apparent, with almost all successful interventions for extending lifespan known to promote autophagy (Carmona-Gutierrez et al, 2019). We are also learning ever more about the major role of autophagy dysfunction in a plethora of ageing diseases, including Alzheimer’s.
Alzheimer’s disease is generally characterised neuropathologically by the loss of neurons and synapses and subsequent atrophy of affected regions, as well as the build-up of extracellular amyloid plaques and intracellular neurofibrillary tangles. Among the markers of the disease, the formation of amyloid plaques especially has long been a key target of Alzheimer’s research as part of the “Amyloid Hypothesis”. Amyloid plaques are formed by agglomerations of a small peptide called Amyloid beta (Aβ), which itself is a fragment broken off from the Amyloid Precursor Protein (APP), a membrane protein very important for synapse formation and neural plasticity (Priller et al., 2006).
Unfortunately, targeting the plaques themselves has yielded little success and research has shifted towards elucidating the core pathological process. Just as weeds will grow back if you give them a trim, only when you attack the root of the disease can you eradicate it once and for all. Autophagy is crucial for maintaining homeostasis in neurones. Just as with any other cells as part of the ageing process, protein aggregates and damaged organelles accumulate in the neurone and must be eliminated by autophagy to avoid fatal cell damage. (Li and Sun, 2017). In a healthy neuron, autophagy serves to mop up dysfunctional APP, Aβ and any other rogue peptides for prompt hydrolysis. Once autophagy is disrupted and if not rescued in time, alongside accumulation of Aβ, these toxic compounds are given free rein in the cell, triggering a positive feedback loop that ultimately results in cellular senescence (Krystal et al., 2020).
Addressing autophagy dysfunction, then, appears key to defeating Alzheimer’s. Samsara’s research is already demonstrating this. “Our best molecules potently induce autophagy and degrade proteins but don’t show any toxicity in the cell,” Hamley notes, “They seem to work in a cell model of Alzheimer’s disease, and we are about to test them in animal models of liver disease after promising results in in vitro models.”
The field is advancing fast, and real results are on the horizon. Hamley is optimistic, “We hope to run a Phase I clinical trial within the next 3 years in a rare genetic liver disease and start to expand to other diseases such as neurodegeneration.” Inducing increased autophagy in patients could provide crucial relief from cellular damage, ameliorating a whole swathe of diseases and helping stave off neurodegeneration. The powerful implications of Samsara’s autophagy research promise great things for fighting disease and healthier ageing. Especially for Alzheimer’s research, the fresh focus on the mechanisms of autophagy provides new hope for effective treatment of many awful diseases.
Special Thanks to Dr. Peter Hamley of Samsara Therapeutics.
Krystal, Hannah L., et al. “Amyloid: From Starch to Finish.” Biological Psychiatry, vol. 87, no. 9, May 2020, pp. e23–e24
Li, Qian, and Miao Sun. “The Role of Autophagy in Alzheimer’s Disease.” Journal of Systems and Integrative Neuroscience, vol. 3, no. 4, 2017
Moreira, Paula I, et al. “Autophagy in Alzheimer’s Disease.” Expert Review of Neurotherapeutics, vol. 10, no. 7, July 2010, pp. 1209–1218
Tran, Michael, and P. Hemachandra Reddy. “Defective Autophagy and Mitophagy in Aging and Alzheimer’s Disease.” Frontiers in Neuroscience, vol. 14, 8 Jan. 2021
Carmona-Gutierrez, Didac, et al. “The Flavonoid 4,4′-Dimethoxychalcone Promotes Autophagy-Dependent Longevity across Species.” Nature Communications, vol. 10, no. 1, 19 Feb. 2019, http://www.nature.com/articles/s41467-019-08555-w.pdf, 10.1038/s41467-019-08555-w. Accessed 26 Feb. 2021.