All ETDs from UAB

Advisory Committee Chair

Matthew S Goldberg

Advisory Committee Members

Erik D Roberson

Rita M Cowell

Andrew B West

David G Standaert

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Parkinson’s disease (PD) is the most common neurogenerative motor disorder, affecting over 10 million people worldwide. Clinically, PD is diagnosed by presentation of hypokinetic movements such as bradykinesia, rigidity, and resting tremor. Additionally, PD patients have non-motor symptoms that include anosmia, constipation, and hypophonia. Current therapeutics have been successful in treating many of the locomotor symptoms, however no therapies stop or slow disease progression and the effectiveness of current medications diminishes as the symptoms invariably become more severe over the course of many years. Histopathologically, PD diagnosis is confirmed postmortem by two pathological hallmarks: 1. loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), 2. proteinatious aggregates termed Lewy bodies and Lewy neurites. Most PD cases are idiopathic, although a subset of cases are linked to genetic mutations. Dominantly inherited gain of function mutations in the SNCA and LRRK2 genes, and recessively inherited loss of function mutations in Parkin, PINK1, and DJ-1 have been causally linked to familial PD. Key observations regarding the molecular and circuit mechanisms involved in PD pathogenesis have helped advance our knowledge of disease mechanisms. First, aggregated alpha synuclein protein is a major component of hallmark Lewy pathology. Second, loss of dopamine innervation of the striatum, the main input nucleus of the BG, results in loss of neuromodulation of striatal spiny projection neurons (SPNs) and dysfunction of the basal ganglia (BG) circuit, which is required for normal movement. Third, mitochondrial dysfunction is common to both idiopathic and genetic forms of PD. Animal models bearing PD causing mutations have been created to investigate underlying disease mechanisms. The PINK1 KO rat model recapitulates key features of PD, including loss of dopaminergic neurons in the substantia nigra, locomotor behavior deficits and mitochondrial dysfunction. However, PINK1 KO rats have not been adequately characterized with respect to alpha synuclein pathology and striatal circuit abnormalities. I utilized histological, biochemical, neurochemical, and electrophysiological approaches to rigorously analyze PINK1 KO rats at multiple ages. I found spontaneous alpha synuclein pathology in different brain regions that increased with age. My electrophysiological analyses revealed increased excitatory drive onto striatal SPNs in PINK1 KO rats. This was accompanied by a significantly altered distribution of alpha-synuclein immunoreactivity at striatal axon terminals. These results greatly expand the utility of PINK1 KO rats as a tool to study the underlying mechanisms by which PINK1 deficiency causes nigrostriatal dysfunction, degeneration, alpha synuclein aggregation and neuronal cell death characteristic of PD.

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