Impact of human alpha-synuclein overexpression on the nigrostriatal dopaminergic neurotransmission

Medina Luque, Jose (2022): Impact of human alpha-synuclein overexpression on the nigrostriatal dopaminergic neurotransmission. Dissertation, LMU München: Fakultät für Biologie

Abstract

Alpha-synuclein is a small 140 amino acid presynaptic protein associated with everal neurodegenerative disorders such as Parkinson’s disease (PD). In idiopathic PD, abnormally misfolded wild-type proteins aggregate in the cytosol of certain neurons, forming what is the main component of Lewy bodies (LBs) - a major PD hallmark. Besides its role in regulating synaptic vesicle functions, alpha-synuclein appears to modulate dopamine (DA), a neurotransmitter particularly important in PD symptoms manifestation. DA can be found sparsely distributed in the brain and is predominantly expressed in midbrain neurons. From the midbrain, two main dopaminergic (DAergic) pathways densely innervate the dorsal portion of the striatum. Degeneration of such DAergic terminals is known to dysregulate DA homeostasis in the striatum. Despite several decades of PD research, the physiological influence of alpha-synuclein on DAergic neurotransmission in the two main areas of the dorsal striatum is still poorly understood. These areas are the dorsomedial striatum (DMS), mainly receiving innervation from the ventral tegmental area, and the dorsolateral striatum (DLS), which receives input from the substantia nigra pars compacta and is more susceptible to neurodegeneration. To clarify how alpha-synuclein may interfere with DAergic neurotransmission in either area, fast-scan cyclic voltammetry experiments were carried out in the DMS and DLS of transgenic mice overexpressing human alpha-synuclein (Tg) at twelve, six and three months of age. Additionally, pharmacological assays, behavioural tasks, and ex vivo immunofluorescence staining were performed to support the electrophysiological ex vivo results. In this thesis, it is hypothesized that due to its intrinsic characteristics, alpha-synuclein preferentially interferes with DA neurotransmission dynamics in the dorsolateral region of the striatum. Data analysis confirmed that overexpression of human alpha-synuclein differentially interfered with normal DA release in the DLS in an age‐dependent manner. At older ages (twelve-month-old Tg mice), decreased evoked DA release and slower DA uptake kinetics were observed. In addition, alterations in dopamine transporter (DAT) distribution, which appeared as increasing amounts of DAT-positive clumps, were found only in the DLS. Moreover, at pre-symptomatic stages (six-month-old) DA neurotransmission appeared to be stabilised before DA disruption. Surprisingly, at younger ages (three-month-old) increased electrically evoked DA release was also recorded in the DLS. Such changes were in line with the motor learning enhancement observed in their behavioural phenotype. In addition, DA uptake appeared to be impaired as evidenced by reduced extracellular DA withdrawal. Further pharmacological experiments demonstrated that such alterations were mediated by DAT. In summary, the present findings indicate that abnormal DAergic neurotransmission and function of DLS can be identified before the onset of structural pathologies in a model of transgenic expression of human alpha-synuclein. Depending on the progression of the pathology, human alpha-synuclein has different impacts on neurotransmission, initially enhancing it but impairing it at later stages. It is here proposed that assessment of DLS function by non-invasive brain imaging and neuropsychological techniques might be relevant in early PD diagnosis and help design appropriate therapeutic interventions

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Fakultät für Biologie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 20. September 2022
• 1. Bericht­erstatter:in: Straka, Hans