Analysis of a murine Pink1 deficiency in serotonergic and dopaminergic neurons in respect of Parkinson´s disease

Hummel, Angelika (2018): Analysis of a murine Pink1 deficiency in serotonergic and dopaminergic neurons in respect of Parkinson´s disease. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)

Abstract

Parkinson’s disease (PD) is one of the most common age-related movement disorders. The main pathological symptoms include a degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNC) and the occurrence of Lewy bodies. As a result, PD patients typically exhibit severe motor symptoms like bradykinesia, tremor and strong gait impairments. Subtle gait impairments are attributed to the “non-motor” symptoms in the pre-motor phase of PD. In addition, PD patients can develop other non-motor symptoms like cognitive and olfactory impairments much earlier than the actual appearance of motor symptoms. Two main forms of PD are described: the familial form, caused by inherited mutations, and the sporadic form, mainly caused by environmental factors and risk genes. Mutations in the human gene Phosphatase and tensin homolog-induced kinase 1 (Pink1) are believed to lead to a loss of function of its kinase domain and is recessively inherited. In order to analyse possible PD related effects of Pink1 deficiency, the murine gene Pink1 was knocked out (KO) by deleting exon 2 & 3 (Pink1_del2/3). The phenotypes of this mouse line exhibiting complete loss of Pink1 function was described in a previous study. These mice exhibited olfactory impairments and decreased serotonergic innervation of the olfactory bulb (OB). Likewise, Pink1_del2/3 mice showed gait impairments, although no neuronal degeneration in SNC was observed in aged mice. In order to understand the underlying mechanism of the Pink1 deficiency-related phenotypes and to uncover possible compensatory mechanisms, transgenic mice with a specific KO of Pink1 in serotonergic or dopaminergic neurons were analysed at young and middle age (mid-aged). Mice underwent a behavioural screening of open field testing (OF) followed by acoustic startle reflex analysis/prepulse inhibition (ASR/PPI), CatWalk testing and olfactory analysis. In addition, dopaminergic neurons were quantified in the SNC and the content of dopamine and serotonin was also measured. Furthermore, the respective metabolites were analysed in different brain regions. Finally, serotonergic innervation in the OB was examined. Overall, young and mid-aged mutant mice of both mouse lines did not display highly significant impairments in the OF, ASR/PPI and olfactory testing. The CatWalk analysis revealed some PD-related parameters affected in mutant mice. The neurotransmitter content did not differ in the different brain regions nor did the number of dopaminergic neurons in the SNC or the serotonergic innervation of the OB. In summary, a murine Pink1 deficiency in serotonergic or dopaminergic neurons did not lead to neuronal degeneration or biochemical changes. In addition, strong PD-related behavioural phenotypes were not observed. Nonetheless, both mouse lines exhibited subtle PD-related gait phenotypes. In conclusion, the serotonergic and dopaminergic system potentially plays a role in the development of PD-related non-motor symptoms upon Pink1 deficiency.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Fakultäten: Graduate School of Systemic Neurosciences (GSN)
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 13. März 2018
• 1. Bericht­erstatter:in: Vogt Weisenhorn, Daniela