Date of Award
Doctor of Philosophy (PhD)
Benoit I. Giasson, Ph.D.
Parkinson’s disease (PD) is an insidious neurodegenerative disorder characterized by a range of motor symptoms which develop predominantly as a consequence of striatal dopamine depletion. The majority of PD cases are idiopathic; however, discoveries of genetic mutations linked to familial forms of PD, including mutations in the genes encoding DJ-1, parkin, and α-synuclein (α-syn), have provided insights into sporadic PD pathogenesis.
Mutations in the gene encoding DJ-1 cause autosomal recessive early-onset PD (AREP). Though the physiological role for DJ-1 is not fully elucidated, it is thought that DJ-1 mutations contribute to disease as a consequence of a loss-of-function. Herein, we show that wild-type (WT) DJ-1 is a relatively stable and soluble homodimer that has diffuse cellular distribution and that can protect mammalian cells against a variety of noxious insults. Pathogenic mutant DJ-1 proteins, L10P, P158DEL, E163K, and L166P display diverse altered biochemical properties. Thus, it is concluded that alterations to distinct DJ-1 residues may specifically affect individual protein functions and may also implicate DJ-1 in a variety of biochemical pathways.
When expressed in mice, human pathogenic mutant A53T α-syn can aggregate and result in fatal motor impairments. It was hypothesized that DJ-1 may act to modulate this effect. Herein, DJ-1 null transgenic animals are generated and assessed for viability against toxic A53T α-syn. However, in double transgenic DJ-1 null mice expressing human pathogenic A53T α-syn, the consequences of DJ-1 deficiency are not apparent and thus it is concluded that DJ-1 may not directly modulate α-syn nor mitigate the deleterious effects of α-syn aggregation in vivo.
Parkin mutations cause AREP which is thought to develop secondary to a loss in parkin function. We discover a novel endogenous parkin mutation in C3H mice, E398Q, which impairs the function of parkin in a similar manner to that of pathogenic missense parkin mutations. It is therefore concluded that C3H mice may serve as suitable models for future studies to assess the effects of parkin loss-of-function in vivo.
Ramsey, Chenere P., "Studies of DJ-1, Parkin and Alpha-Synuclein Give Insights into Plausible Mechanisms for Parkinson's Disease Pathogenesis." (2010). Publicly Accessible Penn Dissertations. 164.