Hermansky-Pudlak protein complexes, AP-3 and BLOC-1, differentially regulate presynaptic composition in the striatum and hippocampus.
Endosomal sorting mechanisms mediated by AP-3 and BLOC-1 are perturbed in Hermansky-Pudlak Syndrome, a human genetic condition characterized by albinism and prolonged bleeding (OMIM #203300). Additionally, mouse models defective in either one of these complexes possess defective synaptic vesicle biogenesis (Newell-Litwa et al., 2009). These synaptic vesicle phenotypes were presumed uniform throughout the brain. However, here we report that AP-3 and BLOC-1 differentially regulate the composition of presynaptic terminals in the striatum and dentate gyrus of the hippocampus. Quantitative immunoelectron microscopy demonstrated that the majority of AP-3 immunoreactivity in both wild-type striatum and hippocampus localizes to presynaptic axonal compartments, where it regulates synaptic vesicle size. In the striatum, loss of AP-3 (Ap3d(mh/mh)) resulted in decreased synaptic vesicle size. In contrast, loss of AP-3 in the dentate gyrus increased synaptic vesicle size, thus suggesting anatomically specific AP-3-regulatory mechanisms. Loss-of-function alleles of BLOC-1, Pldn(pa/pa), and Muted(mu/mu) revealed that this complex acts as a brain-region-specific regulator of AP-3. In fact, BLOC-1 deficiencies selectively reduced AP-3 and AP-3 cargo immunoreactivity in presynaptic compartments within the dentate gyrus both at the light and/or electron microscopy level. However, the striatum did not exhibit these BLOC-1-null phenotypes. Our results demonstrate that distinct brain regions differentially regulate AP-3-dependent synaptic vesicle biogenesis. We propose that anatomically restricted mechanisms within the brain diversify the biogenesis and composition of synaptic vesicles.
Newell-Litwa
Karen
K
Graduate Program in Biochemistry, Cell, and Developmental Biology, Emory University, Atlanta, Georgia 30322, USA.
Chintala
Sreenivasulu
S
Jenkins
Susan
S
Pare
Jean-Francois
JF
McGaha
LeeAnne
L
Smith
Yoland
Y
Faundez
Victor
V
D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D003342:Corpus Striatum / Q000166:cytology* / Q000378:metabolism; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000235:genetics; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron / Q000379:methods; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000648:ultrastructure; D050683:R-SNARE Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013572:Synaptic Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D016708:Synaptophysin / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism / Q000648:ultrastructure; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism*
D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; C113910:Ap3d1 protein, mouse; C513476:Bloc1s6 protein, mouse; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D050683:R-SNARE Proteins; D016708:Synaptophysin; D014157:Transcription Factors