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Congenital muscular dystrophy with laminin α2 chain-deficiency. Initiation of disease and development of treatment

Körner, Zandra LU (2016)
Abstract
Congenital muscle dystrophy type 1A (MDC1A) is a muscle disease caused by
mutations in the LAMA2 gene, encoding the basement membrane protein laminin
α2 chain. MDC1A patients exhibit neonatal onset of muscle weakness, progressive
muscle wasting and hypotonia, joint contractures that mostly affect elbows, hips,
knees and ankles along with scoliosis and delayed motor milestones. Currently,
there is no cure for MDC1A and respiratory failure is the main cause of death.
Patients with complete laminin α2 chain-deficiency have an early onset and also a
more severe muscle phenotype whereas patients with partial loss usually have a
milder disease course. The same genotype-phenotype correlations can be seen in
the... (More)
Congenital muscle dystrophy type 1A (MDC1A) is a muscle disease caused by
mutations in the LAMA2 gene, encoding the basement membrane protein laminin
α2 chain. MDC1A patients exhibit neonatal onset of muscle weakness, progressive
muscle wasting and hypotonia, joint contractures that mostly affect elbows, hips,
knees and ankles along with scoliosis and delayed motor milestones. Currently,
there is no cure for MDC1A and respiratory failure is the main cause of death.
Patients with complete laminin α2 chain-deficiency have an early onset and also a
more severe muscle phenotype whereas patients with partial loss usually have a
milder disease course. The same genotype-phenotype correlations can be seen in
the mouse models of MDC1A. The dy3K/dy3K knock-out model exhibits a much
more severe phenotype than the dy2J/dy2Jmouse model, which expresses a
truncated laminin α2 chain. However, we have not before this thesis known how
early the pathogenesis in the skeletal muscle starts. Here, we demonstrated that
changes in skeletal muscle start with apoptosis already at day one after birth and
inflammation at day four in dy3K/dy3K mice.
Previously, it was demonstrated that the ubiquitin-proteasome system is
upregulated in the dy3K/dy3K mouse muscle. Moreover, by inhibiting the
proteasome by using a lab-bench drug, dy3K/dy3Kmice exhibited reduced muscular
dystrophy. This led us to testing an approved FDA drug, bortezomib, which also
inhibits the proteasome. By using bortezomib we could partially ameliorate the
disease in the dy3K/dy3Kmice with an increased lifespan and improved muscle
function. However, this could not be recapitulated in the dy2J/dy2J mice.
Furthermore, in this thesis we also showed that another pathway for cellular
degradation, the autophagy-lysosome pathway, is upregulated in the
dy3K/dy3Kmouse muscle. By inhibiting the autophagy pathway, dy3K/dy3K mice
exhibited improved muscle morphology and increased lifespan. In summary, I
have shown that there is enhanced proteasome and autophagy activity in MDC1A
muscle and that proteasome and autophagy inhibitors, respectively, can be used to
reduce disease in mice. I hope that our studies can form the basis for the
development of clinically relevant autophagy inhibitors. It may also be worth
testing bortezomib as a possible supportive therapy for MDC1A. Furthermore, our
data suggest that treatment should be initiated as early as possible given that we
detected disease changes already one to four days after birth in mice. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • professor Pedrosa-Domellöf, Fatima, Umeå University
organization
alternative title
Kongenital muskeldystrofi med lamininbrist : Sjukdomsinitiering och utveckling av behandling
publishing date
type
Thesis
publication status
published
subject
keywords
muskeldystrofi, Muscular dystrophy, Autophagy, proteasome, Laminin, MDC1A
pages
118 pages
publisher
Lund University, Faculty of Medicine
defense location
Belfragesalen, BMC D15, Klinikgatan 32, Lund
defense date
2016-09-03 10:00
ISBN
978-91-7619-312-9
language
English
LU publication?
yes
id
2610e14d-b29e-4c7d-8285-5c14a32b1e18
date added to LUP
2016-07-29 14:38:48
date last changed
2016-09-19 08:45:20
@phdthesis{2610e14d-b29e-4c7d-8285-5c14a32b1e18,
  abstract     = {Congenital muscle dystrophy type 1A (MDC1A) is a muscle disease caused by<br/>mutations in the LAMA2 gene, encoding the basement membrane protein laminin<br/>α2 chain. MDC1A patients exhibit neonatal onset of muscle weakness, progressive<br/>muscle wasting and hypotonia, joint contractures that mostly affect elbows, hips,<br/>knees and ankles along with scoliosis and delayed motor milestones. Currently,<br/>there is no cure for MDC1A and respiratory failure is the main cause of death.<br/>Patients with complete laminin α2 chain-deficiency have an early onset and also a<br/>more severe muscle phenotype whereas patients with partial loss usually have a<br/>milder disease course. The same genotype-phenotype correlations can be seen in<br/>the mouse models of MDC1A. The dy3K/dy3K knock-out model exhibits a much<br/>more severe phenotype than the dy2J/dy2Jmouse model, which expresses a<br/>truncated laminin α2 chain. However, we have not before this thesis known how<br/>early the pathogenesis in the skeletal muscle starts. Here, we demonstrated that<br/>changes in skeletal muscle start with apoptosis already at day one after birth and<br/>inflammation at day four in dy3K/dy3K mice.<br/>Previously, it was demonstrated that the ubiquitin-proteasome system is<br/>upregulated in the dy3K/dy3K mouse muscle. Moreover, by inhibiting the<br/>proteasome by using a lab-bench drug, dy3K/dy3Kmice exhibited reduced muscular<br/>dystrophy. This led us to testing an approved FDA drug, bortezomib, which also<br/>inhibits the proteasome. By using bortezomib we could partially ameliorate the<br/>disease in the dy3K/dy3Kmice with an increased lifespan and improved muscle<br/>function. However, this could not be recapitulated in the dy2J/dy2J mice.<br/>Furthermore, in this thesis we also showed that another pathway for cellular<br/>degradation, the autophagy-lysosome pathway, is upregulated in the<br/>dy3K/dy3Kmouse muscle. By inhibiting the autophagy pathway, dy3K/dy3K mice<br/>exhibited improved muscle morphology and increased lifespan. In summary, I<br/>have shown that there is enhanced proteasome and autophagy activity in MDC1A<br/>muscle and that proteasome and autophagy inhibitors, respectively, can be used to<br/>reduce disease in mice. I hope that our studies can form the basis for the<br/>development of clinically relevant autophagy inhibitors. It may also be worth<br/>testing bortezomib as a possible supportive therapy for MDC1A. Furthermore, our<br/>data suggest that treatment should be initiated as early as possible given that we<br/>detected disease changes already one to four days after birth in mice.},
  author       = {Körner, Zandra},
  isbn         = {978-91-7619-312-9},
  keyword      = {muskeldystrofi,Muscular dystrophy,Autophagy,proteasome,Laminin,MDC1A},
  language     = {eng},
  pages        = {118},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  title        = {Congenital muscular dystrophy with laminin α2 chain-deficiency. Initiation of disease and development of treatment},
  year         = {2016},
}