or Parkinson-like diseases;
nevertheless, there is still little understanding of how these genes cause
these conditions," said corresponding author Dr. Hugo Bellen, professor of
molecular and human genetics and neuroscience at Baylor College of Medicine and
an investigator at the Howard Hughes Medical Institute. "In this work, we
have identified new contributors to the disease that we propose can provide a
connection between previously unconnected genes and cellular defects observed
in these diseases."
‘Previous studies have discovered many genes and cellular defects that have independently been associated with Parkinson’s disease. The current study proposes that lipid molecules called ceramides could be the essence that ties all the earlier unconnected discoveries together.’
It all started when Dr. Guang Lin, a postdoctoral
associate in molecular and human genetics who joined the laboratory of Dr.
Bellen started his work on the human PLA2GA6 gene.
PLA2GA6 gene
- Encodes an enzyme called phospholipase that modifies a
type of fats called phospholipids (building blocks of the nervous system)
- Mutations
in the PLA2GA6 gene cause neurodegenerative disorders, including
Parkinsonism
The laboratory focused on investigating what role
phospholipase played in these diseases.
Study
The fly equivalent of the human PLA2GA6 gene is called iPLA2-VIA
which is expressed in neurons and may be other cell types. Lin and his
colleagues developed a fruit fly model of the human condition by knocking out
the iPLA2-VIA gene or making it non-functional.
These mutant fruit flies or those that lack the iPLA2-VIA gene
- Lived
about one third of the lifespan of normal flies and had cellular
characteristics similar to those observed in humans with mutations in
PLA2G6 gene
- They
were healthy when they were young and presented
with age-dependent neurodegeneration
- Studies
showed that there were problems or
defects in their nervous system
- They
took longer to recover from the impact of mechanical stress otherwise
known as bang sensitivity and were paralyzed after the impact compared to
normal fruit flies
- They
found progressive loss of electrical activity in the visual system of the
mutant flies
- The
structure of their neurons under an electron
microscopy showed photoreceptors with many inclusions (absent in normal
cells), structural malformations in most of the mitochondria (often a
feature of Parkinson's disease), and dramatic
enlargement of lysosomes which are intracellular structures involved
in the recycling of membranes and other cellular components.
All the above points indicate that the
iPLA2-VIA gene is important to maintain proper membrane structure and shape of
the neuron.
However, contrary to their expectation, they found
that the lack of iPLA2-VIA gene did not produce any changes in phospholipids,
but rather
increased the amounts of
almost all the ceramides that are important for membrane structure and
function.
It was now evident that the iPLA2-VIA
gene plays a role in the pathway that produces ceramides.
What are Ceramides?
Ceramides are waxy lipid molecules found in
high concentrations within the cell membranes. They make up sphingomyelin,
one of the major lipids in the lipid bilayer. Earlier ceramides and other
sphingolipids were purely supporting structural elements, but now ceramide is
known to participate in a variety of physiological functions including
programmed cell death or apoptosis, cell growth arrest, differentiation, and
proliferation.
Ceramide and
its downstream metabolites are suggested to play a role in a number of
pathological states including cancer, neurodegeneration,
diabetes, microbial pathogenesis, obesity, and
inflammation.
Further studies
When two drugs that blocked ceramide synthesis (desipramine
and myriocin) were tested on the mutant flies, the scientists found that there
were decreased amounts of ceramides as
well as
- Less neurodegeneration
- Less bang sensitivity
- Improved electoretinograms
- Less alteration in the lysosomes
When compared with mutant flies not treated with the drug.
So, it seemed obvious that
the increased amounts of ceramides were instrumental in the structural
and functional changes or defects of the neurons.
The balanced supply of ceramide-derived lipids in the cell
membranes is maintained by reusing (done by retromer proteins) and recycling
(done by lysosomes) them. Retromers bring the lipids back to membranes via
intracellular trafficking. The remaining lipids are recycled back by lysosomes
where they are broken down into ceramides which then go back to the membranes.
In the mutant flies, the increased levels of
ceramide stiffen the membranes. The function
of the retromer is disrupted and there is more lipid shuttling to the lysosomes
to produce more ceramides. This creates a positive-feedback loop that causes
ceramides to accumulate and leads to neurodegeneration in flies lacking the
iPLA2-VIA gene (due to the disruption of the ceramide balance).
The scientists found that the lack of the iPLA2-VIA protein
resulted in less Vps35 and Vps26 (retromer proteins) and caused the disruption
of retromer function, implying a new role for iPLA2-VIA protein, that of
stabilizing retromers and their function. The researchers also confirmed that
the lysosomes actually do extra work and expand due to defective retromers.
Also, restoring retromer function resulted in an improvement of the defects
that were observed in the mutant fruit flies.
The researchers also found that high levels of
alpha-synuclein (a hallmark of Parkinson's disease in vertebrate neurons) lead
to the same changes like retromer dysfunction, lysosomal expansion and ceramide
accumulation. Again, the defects reduced by treatment with the same drugs that
improved the defects observed in fruit flies lacking the iPLA2-VIA gene.
The scientists have thus suggested a new mechanism that can lead to the
Parkinson's disease.
"We show that
loss of phospholipase PLA2G6 leads to ceramide accumulation, defects in
retromer function, progressive lysosome expansion and, finally, to progressive
neurodegeneration with characteristics in common with those observed in
Parkinson's disease. And the same drugs that interfere with ceramide synthesis
also ameliorate the condition. We also found a place for alpha-synuclein in the
disease puzzle," Lin said.
Reference : - Guang Lin1, Pei-Tseng Lee, Kuchuan Chen, Dongxue Mao2, Kai Li Tan, Zhongyuan Zuo1, Wen-Wen Lin1, Liping Wang, Hugo J. Bellen1, "Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain" (2018) Science Direct https://doi.org/10.1016/j.cmet.2018.05.019
Source: Medindia
