Rajalaxmi Natarajan, Ph.D.
June 29, 2017
A team of scientists from many institutions, including the
Jan and Dan Duncan Neurological Research Institute
(NRI) at Texas Children's Hospital have recently published a
paper in the journal PLoS Genetics that links
alterations in sugar metabolism to Zellweger syndrome, a rare
life-threatening genetic disorder.
The study was led by Drs.
Michael Wangler and
Hugo J. Bellen, principal investigators at the NRI and faculty
at the Baylor College of Medicine. Dr. Wangler, a
physician-scientist was inspired to embark on this research when he
encountered a young patient with Zellweger syndrome, also known as
Peroxisomal Biogenesis Disorder (PBD).
Zellweger syndrome/PBD results from defects in genes that
synthesize peroxisomes, essential components of the cell that help
to form and breakdown certain lipids. When peroxisomes do not form
or are defective, people develop a wide range of conditions that
include poor muscle tone, seizures, hearing and vision loss, poor
feeding, skeletal abnormalities, as well as life-threatening
problems in organs such as the liver, heart and kidney. There is no
cure or treatment, other than palliative care.
Until this study, it was postulated that Zellweger syndrome/PBD
was largely a result of improper brain development due to altered
The NRI team collaborated with Dr. James McNew, professor at
Rice University, to employ metabolomics to comprehensively analyze
the levels and profiles of various metabolites such as lipids,
small carbohydrates, amino acids, and cholesterol in fruit flies
that lacked two genes that are essential to make peroxisomes.
The researchers also found that these mutant flies exhibited
most the symptoms such as short life span and locomotor defects,
seen in PBD patients. Thorough analysis confirmed that these
mutants are good animal models to further investigate PDB.
To their surprise, the team found that these mutants exhibited
defects in sugar metabolism and were sensitive to
reductions in dietary sugar. Unlike normal flies, these
mutants could not tolerate a low-sugar diet, as they appeared to be
The researchers found similar alterations in sugar metabolism in
mice that lacked PEX genes, suggesting that
peroxisomal function and glucose metabolism are strongly linked and conserved across species.
The Wangler lab is continuing to investigate how sugar metabolism is
linked to PBD. Since peroxisome dysfunction is also implicated in
other diseases such as Alzheimer's and cancer, they anticipate
their studies into this rare disorder will help provide some beneficial insights for patients with other common diseases as well.