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This hypothesis explains observations made in the
si
/
si
mouse
and in
allele is
one of the most common chicken pigment variants, and is the result
of a polymorphism at the Pmel17 locus.
dominant white
(
I
) chicken pigment mutants. The
I
allele comprises a
three amino acid insertion into the transmembrane region of the
Pmel17 protein. This insertion likely causes problems with Pmel17
folding and trafficking, meaning
11
The
I
I
/* chickens presumably do not
α
have properly formed M
fibres. Like
si
/
si
mouse melanocytes,
melanocytes from
; when
cultured, they die more rapidly than wild-type melanocytes.
I
/
*
chickens are lost prematurely
in vivo
12
Additionally,
melanocytes have significantly diminished sup-
eroxide dismutase (SOD) and glutathione (GSH) l levels.
I
/
*
13
SOD
and GSH restore wild-type-like melanocyte lifespan when added
exogenously to the media of cultured
Melanogenic
intermediates including 5,6-indolequinone are powerful oxidizers
and their inappropriate presence in the cytosol would be expected
to disrupt redox balance within the cell. The oxidative damage and
consequent melanocyte death observed in
I
/
*
melanocytes.
13
si
/
si
mice and
I/*
chickens
can be explained by a lack of M
amyloid fibres, which functions
to keep reactive melanogenic precursor compounds such as
5,6-indolequinone within the melanosome.
α
Figure 9.4
Pmel fibres protect the cell from cytotoxic melanogenic
intermediates. (a) In a wild-type melanosome, melanogenesis
is initiated by the oxidation of tyrosine by tyrosinase. Oxidized
melanogenic intermediates polymerize into melanin along Mα
amyloid fibres, resulting in mature melanosomes. (b) The
si
Pmel17 mutant is unable to make Mα amyloid fibres. Tyrosinase
oxidizes tyrosine; without the Mα fibres to template melanin
synthesis, oxidized melanogenic intermediates are free to leak
out of the melanosome and cause cell death.
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