PRIMA IN MUSCLE AND NERVE OF MICE WITH MUSCULAR DYSTROPHY

1. DOWN-REGULATION OF PRIMA IN MUSCLE AND
NERVE OF MICE WITH MUSCULAR DYSTROPHY BY
MEROSIN DEFICIENCY

2. Lama2dy mice are unable
to produce merosin
(the laminin 2-chain).
They show laminin-2
deficiency and dystrophic
phenotype
Healthy and
Lama2dy mice
Lama2+/? Lama2dy/dy
Lama2+/?
Lama2dy/dy

3. Aberrations in the genes for dystrophin,
dystroglycans, sarcoglycans, laminin-2 and
caveolin 3 produce dystrophic phenotype

4. AChR
CMD1A
AChE

5. AChE COMPONENTS IN MUSCLE AND
MEMBRANE FRACTIONS OF HEALTHY MICE
Whole muscle contains abundant asymmetric and tetrameric AChE;
lipid rafts hold only dimeric AChE; the sarcotubular system displays
principal monomeric, dimeric and tetrameric AChE,
besides RCA-unreactive asymmetric components
RAFT MEMBRANESWHOLE MUSCLE
SARCOPLASMIC
RETICULUM
RCA-
RCA+
RCA = Ricinus communis lectin

6. AChE and BuChE components in skeletal muscle of
normal (NM) and dystrophic Lama2dy mice (DM)
The deficiency of merosin (or
dystrophin) leads to a great
reduction in the content of the
amphiphilic (PRiMA-linked)
AChE and BuChE tetramers
that reside at the sarcolemma
This reduction increases the
availability of acetylcholine,
which possibly favours
desensitization of nAChRs
and impairs muscle
contraction

7. mRNA/-actinmRNA(x10
+6
)
1
10
100
1000
10000
NM
DM
*
E1a E1b E1c E1d HT R BuChE PRiMA
AChE
E1e
P<0.001
Levels of AChE, BuChE and PRiMA mRNAs in normal
(NM) and merosin-deficient dystrophic muscles (DM)

8. Apart from muscle damage, the Lama2dy mouse shows
peripheral neuropathy owing to the laminin-2 deficiency
and the subsequent interruption of the cross-talk
between the motor axon and the Schwann cell

9. The deficiency of merosin
leads to an important
decrease in the content
of PRiMA-linked AChE
and BuChE tetramers
(the G4A forms)
AChE AND BuChE COMPONENTS IN SCIATIC NERVE OF
NORMAL (NN) AND DYSTROPHIC Lama2dy MICE (DN)

10. mRNA/-actinmRNA(x10
+6
)
1
10
100
1000
10000
NN
DN *
E1a E1b E1c E1d HT R BuChE PRiMA
AChE
E1e
Levels of AChE, BuChE and PRiMA transcripts in normal
(NN) and merosin-deficient dystrophic nerves (DN)
NN
DN *
mRNA/-actinmRNA(x10
+6
)
1
10
100
1000
10000
NN
DN *
E1a E1b E1c E1d HT R BuChE PRiMA
AChE
E1e n.d.

11. RelativeexpressionD/N
E1a E1b E1c E1d HT R BuChE PRiMAE1e
AChE
0.1
10
1
Muscle
Nerve
**
**
*
*
Variation of AChE, BuChE and PRiMA mRNAs in
dystrophic muscle and nerve

12. CONCLUSIONS
Dystrophic muscle shows the PRiMA mRNA content decreased by
17-fold. This dramatic reduction prevents the pathological
muscle from being supplied with the required amount of the
sarcolemma-residing PRiMA-linked AChE and BuChE tetramers
The AChE-T mRNA level decreases by 4-fold in dystrophic nerve,
the BuChE mRNA content increases by 3-fold and the PRiMA
mRNA content decreases by 2.5-fold . These variations lead to
decreased AChE activity, increased BuChE activity and
decreased PRiMA-linked AChE and BuChE tetramers. The
up-regulation of BuChE in dystrophic nerve may arise from the
proliferation of immature non-myelinating Schwann cells