ORCID

https://orcid.org/0000-0001-5090-097X

Date of Award

2021

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Biological Sciences

First Advisor

Simon G Moller

Second Advisor

Ales Vancura

Third Advisor

Matteo Ruggiu

Abstract

Parkinson’s disease (PD) is the most common movement disorder and is characterized by neuronal loss and the presence of Lewy bodies in dopaminergic neurons of the substantia nigra pars compacta. PD is a chronic, progressive, and irreversible neurodegenerative disorder associated with the selective loss of dopaminergic neurons. Initially described in an Ayurvedic medical treatise and Galen’s writings, and later by James Parkinson in 1817, the most common symptoms of PD are resting tremors, abnormal posture and gait, and muscle rigidity. Approximately 1 million people are living with PD in the United States and worldwide estimates are between 7 and 10 million. Approximately 5-10% of PD cases are genetic, while the vast majority are sporadic and idiopathic. Mutations in genes such as SNCA, GBA, PRKN, PINK1, DJ-1 and LRRK2 along with environmental factors such as pesticides, gut-bacteria and metal toxicity have been associated with PD. The vast array of possible causes paired with the variance of appearance and rate of progression make the disease difficult to diagnose and study both at a clinical and molecular level. Perhaps the most studied protein in the field of PD is alpha-synuclein (a-syn). Indeed, the interest in the protein was sparked in 1997 by the finding that an alanine to threonine substitution (A53T) in a-syn co-segregated with PD subjects. Both genetic lesions in a-syn and the intrinsic accumulation of the protein in neurons are associated with early- and late-onset PD. A neuropathological hallmark of PD is the presence of insoluble intra-neuronal protein aggregates called Lewy Bodies (LB) which are highly enriched in a-syn. A-syn is an intrinsically disordered and natively unfolded protein with a theoretical size of 14 kDa, which has the propensity to form higher order multimers. Although the genetics of SNCA/a-syn are well known, the physiological function of a-syn is largely unknown as is its ability to influence neurodegeneration and cell death in PD. It has been suggested that a-syn may represent a prime target for future diagnostic and therapeutic intervention strategies. However, to further this notion, it will be important to understand the aggregation dynamics of a-syn and how intermediate a-syn multimers may indeed positively and/or negatively impact the death of neurons in PD.

Download

Share

COinS