By Reshma Kolala, Microbiology, ‘22
Author’s Note: Alzheimer’s disease is one of the most common neurodegenerative disorders, affecting nearly 1 in 9 individuals aged 65 or older. Available current therapies fail to address the underlying pathophysiology of the disorder, focusing on the amelioration of neuronal symptoms that result from Alzheimer’s disease. I was immediately intrigued by the proposal that an existing mechanism for cellular waste removal, chaperone mediated autophagy, could be reinvigorated to remove toxic protein aggregates that are characteristic of an Alzheimer’s diagnosis, thereby targeting a significant contributing factor to the disease. This finding paves the way for new therapies that prevent or delay the onset of Alzheimer’s disease.
“Imagine someone has taken your brain and it’s an old file cabinet and spread all the files over the floor, and you have to put things back together,” describes Greg O’Brian, an award-winning political writer who was diagnosed with Alzheimer’s Disease in 2010. The disorienting feeling described by O’Brian in an interview with Medical Daily is familiar for those diagnosed with Alzheimer’s disease. “My former life no longer exists, and it’s up to me to create a new life,” explains Chris Hannafan in an interview with PBS Newshour, a year after his Alzheimer’s diagnosis. Alzheimer’s disease is a progressive brain disorder that leads to memory loss, developmental disabilities, and cognitive impairment. The cause of the disorder appears to be a culmination of a variety of complex factors that arise as we age, such as the degeneration of neuronal pathways, immune system dysfunction, the buildup of β-amyloid protein, among others [1]. Due to its composite nature, a cure for the neurodegenerative disorder continues to elude the scientific community and treatment remains focused on palliative care, medical care that is focused on relieving and mediating the symptoms of the disorder.
Of the several factors that contribute to an Alzheimer’s diagnosis, scientists have recently focused on a cellular process known as chaperone-mediated autophagy (CMA). Autophagy is a critical and versatile cellular mechanism that allows our cells to degrade or eliminate any unnecessary or damaged components [2]. “Without autophagy, the cell won’t survive,” notes Juleen Zierath, a physiologist at the Karolinska Institute in Stockholm, in an interview with Nature. The autophagy process may vary in each cell and is tailored to meet the demands of a specific cells’ workload. CMA refers to a specific form of autophagy that maintains the delicate balance of proteins in the brain through the use of chaperones. Chaperones or cellular “helpers,” lock onto faulty proteins to prevent buildup before being degraded by the cell. Similar to other cellular processes in our body, CMA is naturally less efficient as we age. This may be attributed to the accumulation of dysfunctional proteins and a compromised ability to respond to stressors over time [2]. When the age-dependent decline of CMA is paired with a neurodegenerative disorder such as Alzheimer’s disease, it has been proposed that the age-related inefficiency of CMA is accelerated. This leads to toxic aggregations, or clumps, of damaged proteins that upset the balance of proteins in the brain and entrap functional proteins, generating more blockage. Without CMA, our cell’s cleanup mechanism, this cellular landfill continues to build and begins to interfere with other critical biological processes.
In April 2021, Dr. Ana Maria Cuervo and her team of researchers at the Albert Einstein College of Medicine published a breakthrough study that investigated the relationship between inefficient CMA and the progression of neurodegenerative diseases in a mouse model of Alzheimer’s disease [3]. Cuervo, the co-study leader and co-director of the Institute for Aging Research at Einstein, noted that “these [mice], similar to the [Alzheimer’s] patients, have decreased memory, develop depression and [have] lack of engagement in general.” Using these mouse models, the first step of the study was to confirm that CMA does, in fact, have an impact on the balance of proteins in the brain. To investigate this, researchers generated a CMA-deficient mouse model through knockout, or removal, of the gene that encodes CMA. When compared against the mice with normal CMA levels, the CMA-deficient mice exhibited characteristics that align with rodent models of Alzheimer’s disease. These characteristics included reduced short-term memory, abnormal motor skills, and other dysfunctional behaviors. By interfering with the cells’ ability to regulate proteins, this finding proves that the proper balance of proteins in the brain contributes to the maintenance of stable neurological function.
The link between CMA deficiency and abnormal neurological symptoms may also be reversed, further emphasizing the importance of CMA in the brain. In a second experiment, researchers examined whether they could observe deficient CMA in mice that were already diagnosed with early Alzheimer’s disease. The results revealed lower levels of CMA activity in the mice that were afflicted with early Alzheimer’s disease. Ultimately, these findings indicated that in the early stages of Alzheimer’s disease, CMA activity is decreased and is likely contributing to the harm caused by aggregated proteins.
With a more concrete understanding of how CMA plays a role in neurological disorders, Cuervo and her team of researchers created a drug that could be used to treat the CMA-related symptoms observed in Alzheimer’s disease. Her vision for this new drug was that “if [we] could increase the removal of these proteins or the cleaning process that occurs normally inside the brain, it might be enough to eliminate toxic proteins.” This pharmaceutical re-energizes a component of the CMA apparatus, allowing a more efficient clearing of protein debris that may otherwise create blockages and eventually manifest in neurological symptoms. In a typical Alzheimer’s patient, “the sheer amount of defective protein overwhelms CMA and essentially cripples it,” Cuervo continues. Essentially, since the levels of faulty protein are markedly higher in Alzheimer’s patients, the CMA process must be functioning optimally. This new drug, CA, acts as a CMA enhancer by interacting with a
receptor, a type of cellular gatekeeper. In a healthy individual, chaperones, or cellular “helpers,” lock onto faulty proteins and guide them to a specific compartment within the cell, the lysosome. A single cell can have hundreds of lysosomes, each of which is tightly sealed from the rest of the cell due to its highly acidic contents. Once the chaperone, faulty protein in hand, has reached the lysosome, it docks to the compartment and releases the protein into the lysosome to be digested. The entry of the faulty proteins into the lysosome is monitored by various cellular gatekeepers present on the surface of the lysosome, one of which is the LAMP2A receptor. Throughout one’s life, the production of the LAMP2A receptor is constant. However, with age, the deterioration of LAMP2A receptors is accelerated. CA specifically targets this challenge by “[restoring] LAMP2A to youthful levels, enabling CMA to get rid of defective proteins so they can’t form those toxic protein clumps” as explained by Cuervo. By increasing the number of LAMP2A receptors, or gates, on the lysosomal surface, researchers were able to increase the channeling of faulty proteins into the lysosome which acts as the garbage disposal of the cell.
This new treatment, despite still being in its early stages of testing, provides an optimistic glance at potentially revolutionizing treatment for those suffering from neurological disorders that are caused by protein aggregation. Although it may be a while before Alzheimer’s patients are free from the daily burden of reorganizing their mental file cabinets, this study sheds light on a previously underscored cellular process and reveals a new avenue for Alzheimer’s research to explore. As Dr. Cuervo concludes, “this [finding] can be considered as an important step forward, or as a very good proof that enhancing cellular cleaning can be a way to develop therapeutics or interventions that can cure Alzheimer’s disease.”
References
- Armstrong RA (2013). What causes alzheimer’s disease?. Folia neuropathologica, 51(3), 169–188. https://doi.org/10.5114/fn.2013.37702
- Bejarano E & Cuervo, AM (2010). Chaperone-mediated autophagy. Proceedings of the American Thoracic Society, 7(1), 29–39. https://doi.org/10.1513/pats.200909-102JS
Bourdenx M, Martín-Segura A, Scrivo A, Rodriguez-Navarro JA, Kaushik S, Tasset I, Diaz A, Storm NJ, Xin Q, Juste YR, Stevenson E, Luengo E, Clement CC, Choi SJ, Krogan NJ, Mosharov EV, Santambrogio L, Grueninger F, Collin L, Swaney DL, Cuervo, AM. (2021). Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome. Cell, 184(10), 2696–2714.e25. https://doi.org/10.1016/j.cell.2021.03.048