Congenital muscular dystrophy with laminin α2 chain-deficiency. Initiation of disease and development of treatment
Kongenital muskeldystrofi med lamininbrist : Sjukdomsinitiering och utveckling av behandling
Författare
Summary, in English
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.
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.
Avdelning/ar
Publiceringsår
2016
Språk
Engelska
Fulltext
Dokumenttyp
Doktorsavhandling
Förlag
Lund University: Faculty of Medicine
Ämne
- Cell and Molecular Biology
Nyckelord
- muskeldystrofi
- Muscular dystrophy
- Autophagy
- proteasome
- Laminin
- MDC1A
Status
Published
Forskningsgrupp
- Muscle Biology
Handledare
ISBN/ISSN/Övrigt
- ISBN: 978-91-7619-312-9
Försvarsdatum
3 september 2016
Försvarstid
10:00
Försvarsplats
Belfragesalen, BMC D15, Klinikgatan 32, Lund
Opponent
- Fatima Pedrosa-Domellöf (professor)