QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, March 18, 2009, 29(11):3365-3373; doi:10.1523/JNEUROSCI.5427-08.2009

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Chung, C. Y. Articles by Isacson, O. Search for Related Content PubMed PubMed Citation Articles by Chung, C. Y. Articles by Isacson, O.

 Previous Article  |  Next Article 

Neurobiology of Disease
Dynamic Changes in Presynaptic and Axonal Transport Proteins Combined with Striatal Neuroinflammation Precede Dopaminergic Neuronal Loss in a Rat Model of AAV -Synucleinopathy

Chee Yeun Chung,^1,2,3 James B. Koprich,^1,2,3 Hasan Siddiqi,^1,3 and Ole Isacson^1,2,3

¹Neuroregeneration Laboratories, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02478, ²Harvard Neurodiscovery Center, Boston, Massachusetts 02114, and ³Morris K. Udall Parkinson's Disease Research Center of Excellence, Belmont, Massachusetts 02478

Correspondence should be addressed to Dr. Ole Isacson and Dr. Chee Yeun Chung, Neuroregeneration Laboratories, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478. Email: isacson{at}hms.harvard.edu; and Email: cychung{at}mclean.harvard.edu

Little is known about key pathological events preceding overt neuronal degeneration in Parkinson's disease (PD) and -synucleinopathy. Recombinant adeno-associated virus 2-mediated delivery of mutant (A53T) human -synuclein into the substantia nigra (SN) under a neuron-specific synapsin promoter resulted in protracted neurodegeneration with significant dopaminergic (DA) neuron loss by 17 weeks. As early as 4 weeks, there was an increase in a dopamine metabolite, DOPAC and histologically, DA axons in the striatum were dystrophic with degenerative bulbs. Before neuronal loss, significant changes were identified in levels of proteins relevant to synaptic transmission and axonal transport in the striatum and the SN. For example, striatal levels of rabphilin 3A and syntaxin were reduced. Levels of anterograde transport motor proteins (KIF1A, KIF1B, KIF2A, and KIF3A) were decreased in the striatum, whereas retrograde motor proteins (dynein, dynamitin, and dynactin1) were increased. In contrast to reduced levels in the striatum, KIF1A and KIF2A levels were elevated in the SN. There were dramatic changes in cytoskeletal protein levels, with actin levels increased and -/-tubulin levels reduced. In addition to these alterations, a neuroinflammatory response was observed at 8 weeks in the striatum, but not in the SN, demonstrated by increased levels of Iba-1, activated microglia and increased levels of proinflammatory cytokines, including IL-1β, IFN- and TNF-. These results demonstrate that changes in proteins relevant to synaptic transmission and axonal transport coupled with neuroinflammation, precede -synuclein-mediated neuronal death. These findings can provide ideas for antecedent biomarkers and presymptomatic interventions in PD.

---

Received Nov. 10, 2008; revised Dec. 26, 2008; accepted Jan. 13, 2009.

Correspondence should be addressed to Dr. Ole Isacson and Dr. Chee Yeun Chung, Neuroregeneration Laboratories, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478. Email: isacson{at}hms.harvard.edu; and Email: cychung{at}mclean.harvard.edu

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help