Holocranohistochemistry enables the visualization of α-synuclein expression in the murine olfactory system and discovery of its systemic anti-microbial effects

Julianna J. Tomlinson, Bojan Shutinoski, Li Dong, Fanyi Meng, Dina Elleithy, Nathalie A. Lengacher, Angela P. Nguyen, Greg O. Cron, Qiubo Jiang, Erik D. Roberson, Robert L. Nussbaum, Nour K. Majbour, Omar M. El-Agnaf, Steffany A. Bennett, Diane C. Lagace, John M. Woulfe, Subash Sad, Earl G. Brown, Michael G. Schlossmacher

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)


Braak and Del Tredici have proposed that typical Parkinson disease (PD) has its origins in the olfactory bulb and gastrointestinal tract. However, the role of the olfactory system has insufficiently been explored in the pathogeneses of PD and Alzheimer disease (AD) in laboratory models. Here, we demonstrate applications of a new method to process mouse heads for microscopy by sectioning, mounting, and staining whole skulls (‘holocranohistochemistry’). This technique permits the visualization of the olfactory system from the nasal cavity to mitral cells and dopamine-producing interneurons of glomeruli in the olfactory bulb. We applied this method to two specific goals: first, to visualize PD- and AD-linked gene expression in the olfactory system, where we detected abundant, endogenous α-synuclein and tau expression in the olfactory epithelium. Furthermore, we observed amyloid-β plaques and proteinase-K-resistant α-synuclein species, respectively, in cranial nerve-I of APP- and human SNCA-over-expressing mice. The second application of the technique was to the modeling of gene–environment interactions in the nasal cavity of mice. We tracked the infection of a neurotropic respiratory-enteric-orphan virus from the nose pad into cranial nerves-I (and -V) and monitored the ensuing brain infection. Given its abundance in the olfactory epithelia, we questioned whether α-synuclein played a role in innate host defenses to modify the outcome of infections. Indeed, Snca-null mice were more likely to succumb to viral encephalitis versus their wild-type littermates. Moreover, using a bacterial sepsis model, Snca-null mice were less able to control infection after intravenous inoculation with Salmonella typhimurium. Together, holocranohistochemistry enabled new discoveries related to α-synuclein expression and its function in mice. Future studies will address: the role of Mapt and mutant SNCA alleles in infection paradigms; the contribution of xenobiotics in the initiation of idiopathic PD; and the safety to the host when systemically targeting α-synuclein by immunotherapy.

Original languageEnglish
Pages (from-to)721-738
Number of pages18
JournalJournal of Neural Transmission
Issue number6
Publication statusPublished - Jun 1 2017
Externally publishedYes


  • APP/Aβ
  • Alzheimer disease
  • Exposome
  • Genome
  • Histology
  • Infection
  • Inoculation
  • MAPT/tau
  • Neuropathology
  • Parkinson disease
  • SNCA/α-synuclein
  • Susceptibility
  • Synucleinopathy

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry


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