Dealing with Ageing

Molecular events identified in biological phase transitions associated with neurogenetic disorders can help therapies

Indian scientists have unraveled the molecular mechanism of protein phase transitions associated with physiological functions and diseases. These unique molecular insights can potentially help the design of therapeutic agents that can prevent pathological phase transitions responsible for fatal neurological diseases.

Highly regulated intracellular phase separation of proteins controls the formation of membrane-less biomolecular condensates that are required for cellular functions. This process, if unregulated, can result in aberrant protein phase transitions into pathological aggregates that are the hallmarks of Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s and other fatal neurodegenerative diseases. This has drawn the attention of several scientists over biological phase separation and the mysteries behind their fundamental mechanism. Owing to the intrinsic flexibility and dynamism of the constituent disordered proteins involved in phase separation, conventional bulk experiments involving multiple molecules are inadequate in capturing the inherent complexity in the process.

Hence scientists from Indian Institute of Science Education and Research (IISER) Mohali, used single-droplet single-molecule FRET (Förster Resonance energy transfer) to shed light on the exquisite inner workings of the liquid-like condensates that are formed through weak, transient but stereospecific intermolecular interactions between highly flexible polypeptide chains possessing multivalency. They found that the structural unwinding exposes the multivalency of polypeptide chains that promotes the transient interactions between flexible protein molecules resulting in biomolecular condensate formation.

The study led by Dr Samrat Mukhopadhyay revealed crucial molecular events during the phase separation of an intrinsically disordered, prion-like, low-complexity domain of Fused in Sarcoma (FUS) – a protein that is associated with ALS.

The single-molecule FRET studies supported by SUPRA programme of Science, Engineering and Research Board (SERB), an attached institutions of Department of Science and Technology (DST) showed that a critical segment of the FUS protein in the monomeric form exists as two structurally distinct subpopulations directed by weak interactions within a protein molecule. During phase separation, a symphony of structural unwinding events turns these interactions into dynamic crosslinks of intermolecular contacts ensuing the formation of liquid droplets. Additionally, a disease-related mutation introduces enhanced structural plasticity engendering greater interchain interactions that can promote liquid-to-solid transitions and accelerate pathological aggregation.

The study published in Nature Communications captured the crucial molecular events associated with phase separation. Such molecular insights can help the design of small molecules that can potentially alter the protein phase behavior leading to a potent therapeutic strategy against devastating neurodegenerative diseases associated with aberrant phase transitions.

Neurological disorders include non-communicable neurological disorders (stroke, headache disorders, epilepsy, cerebral palsy, Alzheimer’s disease and other dementias, brain and central nervous system cancer, Parkinson’s disease, multiple sclerosis, motor neuron diseases, and other neurological disorders), communicable neurological disorders (encephalitis, meningitis, and tetanus), and injury-related neurological disorders (traumatic brain injuries and spinal cord injuries).

It may be noted that “The India State-Level Disease Burden Initiative published in The Lancet Global Health on 14 July 2021” had found out, in its comprehensive estimates of disease burden due to neurological disorders, the following :

• contribution of non-communicable and injury-related neurological disorders to the total disease burden more than doubled in India from 1990 to 2019, whereas the contribution of communicable neurological disorders reduced during this period by three-quarters.

• The burden of non-communicable neurological disorders is increasing in India mainly due to the ageing of the population.

• While communicable diseases contributed to the majority of total neurological disorders burden in children younger than 5 years, non-communicable neurological disorders were the highest contributor in all other age groups.

• Stroke, headache disorders, and epilepsy are the leading contributors to neurological disorders burden in India. The contribution of all neurological disorders to disease burden in India is shown in the table on page 8 of this press release.

• Stroke caused 699,000 deaths in India in 2019, which was 7.4% of the total deaths in the country.

• The burden of many neurological disorders varied considerably between the states, which has significant implications for the policies and programmes to reduce this burden.

•. Among the known risk factors for neurological disorders- burden, high blood pressure, air pollution, dietary risks, high fasting plasma glucose, and high body-mass index are the leading contributors.