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| Immunohistochemistry for alpha-synuclein showing positive staining (brown) of an intraneural Lewy-body in the Substantia nigra in Parkinson's disease. Credit: Wikipedia |
April 27,2015
In studying the molecular biology of brain
development, a team of researchers led by Ludwig Stockholm director Thomas
Perlmann has discovered how disruption of a developmental mechanism alters the
very nerve cells that are most affected in Parkinson's disease. They have also
explained how such disruption induces a lethal dysfunction in the internal,
house-keeping processes of such neurons. The results of their study, which took
nearly four years to complete and involved the exquisitely targeted manipulation
of mouse genes to generate a unique model of the disease, are published in the
current issue of the journal Nature Neuroscience.
"Our model, in many important ways, mimics
the manifestation of Parkinson's in humans and has illuminated what appears to
be a key mechanism of neural decline in this devastating disease," says
Perlmann.
An incurable
neurological disorder, Parkinson's disease (PD) typically begins in
patients as a mere tremor and progresses to a debilitating loss of control over
movement and cognitive
dysfunction, eventually leading to dementia and death. These
symptoms are caused by the gradual wasting away of dopaminergic (DA) neurons, which respond to
the neurotransmitter dopamine and are primarily clustered in the midbrain. They
are critical to control of voluntary movement and the regulation of emotion.
The causes of their wholesale death in PD,
however, remain something of a mystery. DA neurons of patients often contain
odd clots of proteins named Lewy bodies. But it isn't clear whether these
clumps cause neuronal death or are themselves an attempt by the cell to deal
with a deeper dysfunction in breaking down and recycling the components of
misfolded and malfunctioning proteins.
Perlmann and his colleagues were studying Lmx1a
and Lmx1b, a pair of closely related transcription factors—proteins that
control the expression of genes—involved in the development of DA neurons.
These developmentally vital transcription factors persist even after the
neurons have matured. To find out what they do in mature neurons, the
researchers painstakingly engineered mice in a manner that permitted them to
delete the Lmx1a/b genes in DA neurons alone, and to do so at a time of their
choosing.
"When we looked at the DA neurons that
lacked the Lmx1a/b genes, those in adult mice had many of the same abnormalities
you see in various stages of PD," says Perlmann. "The nerve fibers
that extend out from these neurons to others were degenerating, as were the
nerve terminals, and this was happening long before the neurons died."
Further, the engineered mice were shown in behavioral tests to have poor memory
and motor control, both of which are symptoms of PD.
The researchers found that midbrain DA neurons
from patients with PD express far lower levels of the Lmx1b protein than do
their non-PD counterparts. So the researchers looked into how the loss of Lmx1a
and b was affecting the neurons. They found that Lmx1b, in particular, controls
the expression of a number of genes central to a process known as lysosomal
autophagy by which cells break down abnormally folded protein molecules so that
they don't poison the cell. This process is believed to be compromised in PD.
Treating young mice with a compound that boosts
autophagy reversed the neural degeneration induced by loss of Lmx1b. In sum,
the studies suggest the loss of Lmx1b expression is probably involved in the
development of PD, that it induces a decline in the function of DA neurons by
undermining autophagy and that this gradually sickens and then kills the DA
neuron.
Perlmann and his colleagues are now using their
unique animal model to research the details of Lmx1b's regulation of
autophagy—such as the networks of genes it activates. The researchers are also
looking into ways to prevent the loss of Lmx1b in PD and if such approaches
could be of benefit in treating the disease. The process of autophagy also has
relevance in cancer.
Explore further: Mitochondria are
altered in human cell model of Parkinson's disease
More information:
Dopaminergic control of autophagic-lysosomal function implicates Lmx1b in
Parkinson's disease, Nature Neuroscience, DOI: 10.1038/nn.4004
http://medicalxpress.com/news/2015-04-key-factor-neural-death-parkinson.html
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