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Aberrant Plasma Membrane in NPA Disease
2005) and that the deleterious consequences observed in this
work upon ASM deficiency (i.e., aberrant distribution and
reduced internalization) seem to affect DRM-enriched mol-
ecules specifically suggest the involvement of a particular
membrane microenvironment in the pathology of NPA.
However, it is possible that the effects of SM accumulation
are independent of its clustering in DRMs. We envision that
changes in the thickness and fluidity of the plasma mem-
brane due to SM increase could alter, per se, not only the
retrieval of membrane but also the reception and transmis-
sion of signals across it. In this regard, it is important to
highlight that ASM deficiency not only increases brain SM
levels but also those of its metabolites like sphingosylphos-
phorylcholine, which have been shown to participate in
signaling events regulating cellular responses such as differ-
entiation, survival, or cytoskeletal rearrangements (Kostenis,
2004). Taken together all the above, further research appears
essential to address how SM metabolism defects influence
the trafficking and distribution of other lipids and the func-
tional properties of membranes in neuronal cells.
ACKNOWLEDGMENTS
W e thank G. Vand erhoeven for excellent techn ical assistance and Dr. C. G.
D otti (Leu ven, Belgium ) for constant suppo rt. W e are gratefu l to Dr. E. H .
Schuchm an (N ew Y ork, N Y) for kindly providing us w ith A Sm ase ± mice
couples and to D rs. A . A guzzi (Zurich , Sw itzerland), P. K eller (M ax Planck
Institu te of M olecular Cell B iology, D resden , G erm any), T. Kobayashi (Tokyo,
Jap an), and A. Jaffe (L ab oratory for M olecular Cell Biology, U n iversity Col-
lege Lon d on, U nited K ingdom ) for the gift of the anti PrPC antibody, the
GPI-G FP con stru ct, Lysen in-M BP, and the RhoA (LS63) clone, respectively.
This w ork w as sup po rted by research grants from the N atio nal N iem ann Pick
D isease Fo und ation and Telethon-Italy (G rant G G P02245) to M .D.L. and from
the "Fo nd s v oor W etenschappelijk O nderzoek-V laanderen; Project G .0405.02" to
P.P.V.V.
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