Is eating junk always unhealthy? Well, not when neurons do it! According to a recent study by scientists at Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) Bangalore, when neurons consume high amounts of unwanted toxic protein aggregates through a process called autophagy, it can have therapeutic implications in the treatment of neurodegenerative disorders like Parkinson’s and Alzheimer’s diseases. The study was published in the journal Autophagy.
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. A hallmark of PD is the accumulation of a misfolded protein α‑synuclein in the brain. The accumulation is aggravated by impairment in neuron’s autophagy machinery, which otherwise helps keep a check on the buildup of unwanted or misfolded proteins. Autophagy, literally self-eating, is a cleaning process employed by cells, that helps degrade unwanted and worn-out cytoplasmic contents in lysosomes.
To understand the relevance of autophagy in disease models, researchers at JNCASR screened several pharmacologically-active drug-like compounds that could clear α‑synuclein aggregates to restore viability in yeast and mammalian cell lines. “Out of a total 1280 compounds screened in duplicates, five showed clearance of protein aggregates by increased autophagy,” says Ravi Manjithaya, principal investigator of the study.
One of these compounds called 6‑Bio was extremely potent in modulating autophagy in a dose-dependent manner. 6‑Bio diffused into the cells passively where it enhanced the fusion of autophagosomes with lysosomes. Furthermore, 6‑Bio administration resulted in clearance of toxic α‑synuclein aggregates in mouse brains leading to neuroprotection. These mice also demonstrated improved motor coordination and locomotion abilities. “Using small molecules, our target was two-fold – to get a deeper insight into the mechanisms of autophagy and to provide a proof-of-principle that autophagy restoration can cure the ailment in disease models,” he adds.
In PD, symptoms start appearing only after 60 – 80% of the neurons are lost. The late appearance of the first signs of the disease makes it all the more debilitating. “With an increase in life expectancy, this disease of the elderly is on the rise, adding to the economic burden substantially,” cautions Manjithaya.
“Currently available Parkinson’s disease therapeutics, L‑DOPA (Levodopa) and acetylcholine esterase inhibitors, only provide symptomatic relief by alleviating functional disability. Similarly, stem cell-based therapeutics and fetal stem cell transplantation have not yielded encouraging results in clinical trials worldwide,” says Rajnish Chaturvedi, Senior Scientist at CSIR- Indian Institute of Toxicology Research (IITR), Lucknow. “It is the need of the hour to develop such therapeutics which not only provide symptomatic relief but also clear the misfolded proteins from the brain. It is remarkable that activation of autophagy not only results in the presence of increased number of dopamine-producing neurons but also improves behavioural phenotypes in 6‑Bio treated Parkinson’s disease mice,” he adds.
“Since most cases of PD are sporadic, manipulation of autophagy for aggregate clearance utilising bioactive compounds as a tool can be promising. We have some interesting phenotypes from this study and are currently working to get a mechanistic handle on other potential modulators,” says Manjithaya.
“Given the ability of 6‑Bio to cross blood brain barrier, this study has implications for a variety of neurodegenerative disorders,” says Nallathambi Jeyabalan, Senior Scientist at Narayana Nethralaya Foundation, Bangalore. “It would be interesting to know if 6‑Bio reaches the brain owing to its small size or by increasing the barrier permeability,” says Chaturvedi. “With further advancements in the development of 6‑Bio as a drug molecule, it can also find potential applications in the treatment of various eye and liver infections where autophagy is impaired,” Jeyabalan adds.