BENGALURU: Researchers at the National Centre for Biological Sciences (NCBS), Bengaluru, have identified how abnormal levels of specific lipids in the brain lead to neurological defects in patients with Lowe Syndrome (LS), a rare genetic disorder that affects the brain, eyes, and kidneys.
The study marks the first time in India that scientists have developed a model system to study LS at the cellular level and design potential personalised therapies. The work was carried out in collaboration with the Rohini Nilekani Centre for Brain and Mind (CBM) and is published in EMBO Molecular Medicine.
LS is caused by mutations in a gene that produces an enzyme called OCRL, which helps regulate phospholipids — molecules essential for maintaining cell structure and communication. As per researchers, in LS patients, the enzyme fails to break down a lipid known as PI(4,5)P2, leading to its abnormal buildup.
“Elevated PI(4,5)P2 levels interfere with smooth communication between nerve cells and trigger an early increase in astrocytes, another type of brain cell. This imbalance disrupts normal brain development,” explained Yojet Sharma, PhD scholar at NCBS and lead author of the study.
To understand how these changes occur, researchers used stem cell technology to convert blood samples from an affected family into human-induced pluripotent stem cells (iPSCs). These cells were then grown into three-dimensional brain organoids — miniature versions of the human brain that mimic its early growth and organisation.
One month into the experiment, the scientists observed that neurons derived from LS patients were not sending electrical signals to each other effectively, while astrocyte numbers were unusually high. When the team treated the organoids with a repurposed drug, lipid levels dropped and neuronal communication improved within a week.
According to NCBS Professor Raghu Padinjat, who co-authored the paper, the findings could pave the way for better understanding and treatment of rare brain disorders. “Our model shows how stem cell–based systems can recreate early brain development in the lab and help researchers and clinicians explore new therapeutic options for diseases like LS,” he said.
Lowe Syndrome affects about one in 5 lakh people globally, with its prevalence in India yet to be determined.
The study marks the first time in India that scientists have developed a model system to study LS at the cellular level and design potential personalised therapies. The work was carried out in collaboration with the Rohini Nilekani Centre for Brain and Mind (CBM) and is published in EMBO Molecular Medicine.
LS is caused by mutations in a gene that produces an enzyme called OCRL, which helps regulate phospholipids — molecules essential for maintaining cell structure and communication. As per researchers, in LS patients, the enzyme fails to break down a lipid known as PI(4,5)P2, leading to its abnormal buildup.
“Elevated PI(4,5)P2 levels interfere with smooth communication between nerve cells and trigger an early increase in astrocytes, another type of brain cell. This imbalance disrupts normal brain development,” explained Yojet Sharma, PhD scholar at NCBS and lead author of the study.
To understand how these changes occur, researchers used stem cell technology to convert blood samples from an affected family into human-induced pluripotent stem cells (iPSCs). These cells were then grown into three-dimensional brain organoids — miniature versions of the human brain that mimic its early growth and organisation.
One month into the experiment, the scientists observed that neurons derived from LS patients were not sending electrical signals to each other effectively, while astrocyte numbers were unusually high. When the team treated the organoids with a repurposed drug, lipid levels dropped and neuronal communication improved within a week.
According to NCBS Professor Raghu Padinjat, who co-authored the paper, the findings could pave the way for better understanding and treatment of rare brain disorders. “Our model shows how stem cell–based systems can recreate early brain development in the lab and help researchers and clinicians explore new therapeutic options for diseases like LS,” he said.
Lowe Syndrome affects about one in 5 lakh people globally, with its prevalence in India yet to be determined.
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