Parkinson’s Disease (PD) is the second most common neurodegenerative disease, affecting roughly 5 million people worldwide. Levodopa (L-DOPA) is the gold-standard treatment for PD patients, but after about 5-7 years of usage many patients develop a serious side effect known as levodopa-induced dyskinesia (LID). With onset, patients experience choreiform and dystonic movements, drastically reducing quality of life. We are working on repurposing sub-anesthetic ketamine to treat LID and have shown great efficacy in the rodent PD models to both reduce established LID and attenuate the development of LID, work that is currently progressing to a Phase II clinical trial. How ketamine works in addition to the well-known N-Methyl-D-aspartate (NMDA) receptor antagonism, is still unclear due to its multi-functional nature. Thus, this summer we are using the pan-opioid receptor antagonist naloxone to determine if opioid receptor activation by ketamine contributes to the lessening of abnormal involuntary movements (AIMs) associated with LID. Lesioning unilaterally with 6-hydroxydopamine (6-OHDA) to establish PD in rodents, we can test for lesion efficacy by administering amphetamine and have included rats with ≥4 net ipsilateral amphetamine-induced rotation scores into the study (mean ± SEM: 6.44±0.49). The baseline dyskinesia being used to group animals: 35.9±1.78 mean AIMs ± SEM. Three 10-hr treatment groups (all i.p. injections) – vehicle, naloxone, or naloxone (3 mg/kg) + ketamine (20 mg/kg) – with n=7 each were dosed with L-DOPA (6 mg/kg) according to our established model of LID, and AIMs were scored. Pilot analysis to be presented at the conclusion of summer.

Krabbe disease (KD) is a lysosomal storage disorder that causes extensive demyelination in the central and peripheral nervous systems. KD is caused by a loss-of-function mutation in lysosomal hydrolase, galactosylceramidase (GALC), which is responsible for breaking down galactosylceramide (GalCer) into galactose and ceramide. Lack of the GALC results in the accumulation of GalCer and its toxic byproduct, psychosine. However, accumulation of these two substrates is not sufficient to explain the severity of the disease. We are using well-characterized Schwann cells (SCs) in a specific GALC-ablated conditional mouse model, that presents with pathologies of KD in the peripheral nervous system. This allow us to study what cellular mechanisms are altered by the lack of GALC function that further contributes to disease pathogenesis and severity. Based on recent results from electron microscopy, western blotting, and immunohistochemistry, we detected changes in autophagy components in the SCs of pre-symptomatic mutant mice. We hypothesized that autophagy is affected by the lack of GALC and it contributes to disease pathogenesis. To test this, we deleted Atg7 from our KD mouse model and are currently characterizing myelin abnormalities and disease severity by semithin quantification and western blots.

Aging is characterized by the decline and deterioration of cells and organs due to the accumulation of macromolecular and organelle damage. There is an increase in intralysosomal concentration of free radicals, age pigment lipofuscin, and a deficiency of lysosomal protein degradation as aging progress. The ortholog of gene collapsin response mediator protein -2(CRMP-2) in C. elegans is UNC-33. UNC-33 acts as an important modulator of neurite outgrowth and axonal guidance, membrane protein trafficking, and neuronal excitability. There are three isoforms of the UNC-33: small, medium, and large. However, only UNC-33L(large) acts to promote trafficking of axonal proteins. In this study, we hypothesize that nematodes lacking all three isoforms will exhibit premature death, reduced locomotion, and defective pharyngeal pumping. Additionally, we hypothesize that the expression of the isoform UNC-33L will be sufficient to rescue the shorter lifespan, defective pharyngeal pumping, and reduced locomotion found in unc-33(mn407) mutants. To analyze the role of UNC-33 in aging, we used unc-33(mn407), unc-33(mn407) with the unc-33L transgene, and N2 strains. To test the hypotheses, the lifespan of 20 synchronized young adults per strain was assessed by looking at survival every 24 hours until death. To test age-related markers, liquid locomotion and pharyngeal pumping of each strain were assessed in four-day increments, for a total of 12 days. Based on our predictions, we expect to see decreased lifespan, locomotion, and pharyngeal pumping in unc-33(mn407). Additionally, we predict a rescue of these three different phenotypes when the isoform UNC-33L is present.

Pre-synaptic alpha-2 adrenergic receptors, commonly recognized for their role in catecholamine induced vasoconstriction, may also contribute to the progression of neurodegeneration. Hyperactive In the central nervous system, these receptors regulate changes in the interstitial space through mediating norepinephrine levels. When the interstitial space is reduced, metabolic waste clearance such as Amyloid-beta is not as efficient. Additionally, alpha-2 adrenergic receptors are found in the hypothalamus, locus coeruleus (LC), pancreas, kidney, and adipose tissue, requiring a holistic view to accurately identify the mechanistic role of alpha-2 adrenergic receptor activity in AD. In humans, the number and activity level of alpha-2 adrenergic receptors has been suggested to play a role in arousal and alertness. We are interested in investigating whether Apolipoprotein (APOE) isoforms reflect behavioral and physiological differences in mice animal models. The aims of this study are to image hypothalamic, LC, adipose, and livers from homozygous APOE-epsilon3 and APOE-epsilon4 male and female mice to determine if the amount of alpha-2 adrenergic receptors in the tissues correlate to behavioral and physiological effects such as adipose index, cognitive measures, or weight trajectories. These results will establish the foundation for more accurate and translatable testing of AD treatments in the future.