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Author Notes:

Address correspondence to: Victor Faundez Department of Cell Biology Emory University School of Medicine 615 Michael Street, Room 446 Atlanta, GA 30322 Telephone: 404-727-3900 Fax: 404-727-6256 faundez@cellbio.emory.edu

These authors contributed equally to this work.

Subjects:

Research Funding:

National Institute of Neurological Disorders and Stroke : NINDS

National Institute of General Medical Sciences : NIGMS

Keywords:

  • Synapse
  • Synaptic
  • dentate gyrus
  • striatum
  • presynaptic regulation
  • Membrane

Hermansky-Pudlak Protein Complexes, AP-3 and BLOC-1, Differentially Regulate Presynaptic Composition in the Striatum and Hippocampus

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Journal Title:

Journal of Neuroscience Nursing

Volume:

Volume 30, Number 3

Publisher:

, Pages 820-831

Type of Work:

Article | Post-print: After Peer Review

Abstract:

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 pre-synaptic 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 pre-synaptic axonal compartments, where it regulates synaptic vesicle size. In the striatum, loss of AP-3 (Ap3dmh/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, Pldnpa/pa and Mutedmu/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 pre-synaptic 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.
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