Parkinson's disease (PD) is the prototypic degenerative disease of the dopamine (DA) neuronal system. The progressive loss of nigrostriatal DA neurons gradually leads to a severe movement disorder characterized by tremor, rigidity, bradykinesia and impaired balance. PD accounts for significant morbidity and mortality among veterans and the general population. It is not widely appreciated but the serotonin (5HT) neuronal system is also severely impacted in PD. Brains from individuals with PD have significantly lower levels of 5HT, reduced 5HT synthesis and turnover, reductions in the amount of tryptophan hydroxylase (TPH2) and losses in the number of intact 5HT neurons. Decrements in 5HT neurochemical function are highly significant in light of the fact that approximately 80% of PD patients suffer from co-morbid neuropsychiatric conditions like depression, sleep disorders, anxiety and dementia. Many of these conditions have been linked to dysfunctional 5HT neurochemistry. L-DOPA is the gold-standard pharmacotherapy for PD. L-DOPA enters the brain and is converted to DA by the ubiquitous L-aromatic amino acid decarboxylase (L-AADC). This treatment increases DA in all cells expressing L-AADC to include DA neurons, as desired, as well as in 5HT and other neurons. This inappropriate deposition of DA within 5HT neurons can alter their neurochemical function and subject them to heightened oxidative stress from non- enzymatic breakdown products of L-DOPA and DA. The non-motor symptoms of PD, whether related to the disease process or L-DOPA-induced, are not trivial and contribute to worsened disability, impaired quality of life and shortened life expectancy. Therefore, a better understanding of the mechanisms responsible for the non-motor symptoms that accompany the motor problems of PD is called for urgently. A growing body of evidence has established a clear link between protein misfolding and aggregation to cytotoxicity and neurodegenerative conditions. Protein cysteine residues can be viewed as cellular redox sensors. Modification of cysteines by oxidation can change protein conformation in a rapid and reversible way as part of a controlled signaling process. Persistent oxidative stress can overwhelm cellular mechanisms that maintain the delicate balance between protein synthesis and degradation, leading eventually to cellular damage and death. TPH2, in addition to being the initial and rate limiting enzyme in the synthesis of 5HT and a phenotypic marker for 5HT neurons, is a cysteine-rich protein. TPH2 is extremely unstable and can undergo misfolding and aggregation upon mild oxidation, much as is seen with other proteins within DA neurons in PD. We propose that TPH2 targets 5HT neurons for damage as a result PD-related oxidative stress and that L-DOPA can accentuate this process. We will apply a variety of molecular and cell biological approaches along with the use of a unique mouse lacking TPH2 to assess the role of TPH2 in 5HT neuronal compromise seen in PD.

Public Health Relevance

Project Narrative Parkinson's disease (PD) is a progressive neurodegenerative disorder that accounts for significant morbidity and mortality among Veterans and the general population. PD is the seventh leading cause of death in the US. The hallmark motor symptoms of PD can be traced to the loss of dopamine (DA) neurons of the nigrostriatal pathway. However, it is not nearly as widely appreciated that the majority of individuals with PD also suffer from co-morbid neuropsychiatric conditions such as depression, anxiety and sleep disorders. The neurobiological mechanisms responsible for these non-motor symptoms of PD are not known but many indicators point to loss of function in 5HT neurons. It has been suggested that 5HT neurons are severely damaged in PD but very little research has been dedicated to achieving a better understanding of this process. In light of the prevalence of co-morbid neuropsychiatric problems in PD and knowing that these non-motor symptoms contribute to worsened disability, impaired quality of life and shortened life expectancy, it is imperative that we achieve a better understanding of the how the 5HT neuronal system is impacted in this neurodegenerative disorder.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01RX000458-01A2
Application #
8277532
Study Section
Blank (RRD6)
Project Start
2012-10-01
Project End
2016-09-30
Budget Start
2012-10-01
Budget End
2016-09-30
Support Year
1
Fiscal Year
2012
Total Cost
Indirect Cost
Name
John D Dingell VA Medical Center
Department
Type
DUNS #
002643443
City
Detroit
State
MI
Country
United States
Zip Code
48201
Komnenov, Dragana; Solarewicz, Julia Z; Afzal, Fareeza et al. (2016) Intermittent hypoxia promotes recovery of respiratory motor function in spinal cord-injured mice depleted of serotonin in the central nervous system. J Appl Physiol (1985) 121:545-57
Anneken, John H; Angoa-Pérez, Mariana; Kuhn, Donald M (2015) 3,4-Methylenedioxypyrovalerone prevents while methylone enhances methamphetamine-induced damage to dopamine nerve endings: ?-ketoamphetamine modulation of neurotoxicity by the dopamine transporter. J Neurochem 133:211-22
Angoa-Pérez, Mariana; Kuhn, Donald M (2015) Neuroanatomical dichotomy of sexual behaviors in rodents: a special emphasis on brain serotonin. Behav Pharmacol 26:595-606
Angoa-Pérez, Mariana; Herrera-Mundo, Nieves; Kane, Michael J et al. (2015) Brain serotonin signaling does not determine sexual preference in male mice. PLoS One 10:e0118603
Angoa-Pérez, Mariana; Kuhn, Donald M (2015) Neuronal serotonin in the regulation of maternal behavior in rodents. Neurotransmitter (Houst) 2:
Solarewicz, Julia Z; Angoa-Perez, Mariana; Kuhn, Donald M et al. (2015) The sleep-wake cycle and motor activity, but not temperature, are disrupted over the light-dark cycle in mice genetically depleted of serotonin. Am J Physiol Regul Integr Comp Physiol 308:R10-7
Hickner, Stephen; Hussain, Najaah; Angoa-Perez, Mariana et al. (2014) Ventilatory long-term facilitation is evident after initial and repeated exposure to intermittent hypoxia in mice genetically depleted of brain serotonin. J Appl Physiol (1985) 116:240-50
Angoa-Pérez, Mariana; Kane, Michael J; Briggs, Denise I et al. (2014) Mice genetically depleted of brain serotonin do not display a depression-like behavioral phenotype. ACS Chem Neurosci 5:908-19
Angoa-Pérez, Mariana; Kane, Michael J; Herrera-Mundo, Nieves et al. (2014) Effects of combined treatment with mephedrone and methamphetamine or 3,4-methylenedioxymethamphetamine on serotonin nerve endings of the hippocampus. Life Sci 97:31-6
Angoa-Pérez, M; Kane, M J; Sykes, C E et al. (2014) Brain serotonin determines maternal behavior and offspring survival. Genes Brain Behav 13:579-91

Showing the most recent 10 out of 17 publications