Objective/Rationale:
Compelling evidence demonstrated that a dysfunction of the locus coeruleus (LC)-
noradrenaline (NE) system in the brain not only contributes to alterations in
cognitive and motor function appearing in Parkinson’s disease (PD) patients, but
also exacerbates the degeneration of nigrostriatal dopaminergic neurons. While
currently the dopamine system remains to be the main therapeutic target,
correcting the dysfunctional LC-NE system in PD would improve the efficacy of the
current therapies.
Project Description:
This study employs a novel genetic approach by microinjection of lentiviral-cDNAs
of transcription factors Phox2a, Phox2b, Hand2 or Gata3, either alone or in
combination, into the LC region of VMAT2-deficient PD pre-clinical models. The noradrenergic phenotype expression in the LC, hippocampus, frontal cortex and amygdala will be examined by real-time PCR, Western blotting and immunostaining. Further, in these gene-transferred PD pre-clinical models, the NE in the hippocampus and frontal cortex and dopamine levels in the striatum-nigra will be measured by microdialysis, and behavioral tests will be
performed to check the functional changes and the beneficial effects on the
dopamine system.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Although deficiencies of noradrenergic neurons in PD are well known, the
underlying mechanisms remain obscure and therapeutic interventions to reverse
these deficiencies are limited. The results of this project will facilitate the
development of molecular therapeutic strategies for PD. Also, these results will
provide new insight into causal interaction between transcription factor genes and
LC neurons during the progression of PD.
Anticipated Outcome:
We hypothesize that overexpression of transcription factors Phox2, Hand2 and
Gata3 in the LC, either alone or in combination, will vigorously increase
noradrenergic phenotype expression, which consequently restores the
noradrenergic function in Parkinsonian brains. These restored LC-NE system
further facilitate the recovery of the dopamine system.
Final Outcome
Transcription factors are specialized proteins that turn on and off the production of other proteins in the cell. In this study, we examined possible effects of excessive production of transcription factors in the locus coeruleus -- one of the regions of the brain involved in Parkinson's disease (PD) -- in pre-clinical models with Parkinson's features. We aimed to evaluate how the excessive production of transcription factors affects the production of norepinephrine and dopamine, brain chemicals involved in PD. After the production of transcription factors was induced in the locus coeruleus, we evaluated several outcomes in our models: the production of these transcription factors as well as dopamine β-hydroxylase (DBH) and tyrosine hydroxylase (TH) -- proteins that control the production of dopamine and norepinephrine -- along with movement, anxiety and cognition.
We found that excessive production of these transcription factors in the locus coeruleus significantly affected the production of DBH and TH in this and other brain regions, such as the striatum, substantial nigra, hippocampus and frontal cortex. Moreover, excessive production of these transcription factors improved cognition and reduced anxiety. This study demonstrates a positive effect of excessive production of transcription factors in the locus coeruleus on the function of brain regions fueled by dopamine and norepinephrine.
May 2014