Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily characterized by motor symptoms, including tremors, impaired balance, and bradykinesia. In addition to these motor symptoms, many individuals with PD also experience a range of non-motor symptoms such as dementia, depression, and sleep disturbances, which significantly affect their quality of life. Two key pathological features of PD are the degeneration of dopaminergic neurons in the nigrostriatal pathway and the accumulation of Lewy bodies—aggregates primarily composed of α-synuclein (α-syn) protein. Neuroinflammation is also recognized as a critical hallmark of PD, and neurodegeneration in general, likely contributing to neuronal damage and disease progression. Interestingly, members of the chitinase protein family, particularly chitinase-3-like protein-1 (CHI3L1), exhibit elevated levels in a number of neurodegenerative conditions and have been implicated in various inflammatory pathways. To explore the role of CHI3L1 in PD, CHI3L1’s expression was examined in both postmortem brain tissue from PD patients and in the recombinant adeno-associated virus (rAAV)-mediated α-syn overexpression rat model of PD. Additionally, characterization of different AAVs was undertaken in efforts to manipulate CHI3L1 expression specifically in astrocytes for future studies, as CHI3L1 is an astrocytic protein. In human post-mortem samples, protein levels of intracellular, extracellular, and total CHI3L1 were significantly higher in the substantia nigra pars compacta (SNpc) samples from PD patients compared to non-diseased controls. Additionally, qualitative histological analyses reveal elevated CHI3L1 expression in the α-syn rat model within the substantia nigra. The presence of elevated CHI3L1 in PD raises the question: Is this increase causal or merely a consequence of the disease? Ongoing research seeks to address this by identifying an astrocyte-specific viral capsid allowing for altering astrocytic CHI3L1 expression in the α-syn model. These efforts aim to distinguish cause from consequence, and uncover the underlying mechanisms driving the association between CHI3L1 levels and neurodegeneration.

Parkinson's disease is characterized as the loss of dopaminergic neurons in the substantia nigra, leading to striatal dopamine insufficiency that contribute to the motor signs and symptoms of the disorder, which include tremor, rigidity, akinesia, and postural instability. Despite increasing advancements to discover new approaches to alleviate the motor dysfunctions in the disorder, there are several setbacks with the current treatment options on the market. In this study, we look at using an optical technique, known as fiber photometry, to directly measure neural activity in particular brain regions of interest to understand the neurobiological changes associated with the disorder. Here, we use GCaMP, a genetically encoded calcium indicator, to measure calcium-dependent transients in the striatum and compare a lesioned nigrostriatal pathway, induced by 6-hydroxydopamine (6-OHDA), to an intact hemisphere of hemiparkinsonian animal models.

The kynurenine pathway (KP) is a biosynthetic pathway for the catabolism of tryptophan, the amino acid precursor to serotonin. The KP has been linked to neuroinflammation, as inflammatory agents upregulate an early enzyme in the pathway (Davis & Liu, 2015; Wang et al., 2009). In addition, the metabolite quinolinic acid (QA) has been found to induce tau phosphorylation and excess glutamate release, inducing further neuroinflammation (Guillemin, 2012; Rahman et al., 2009). However, in the presence of 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD), the KP shifts away from QA production towards that of picolinic acid (PA), a metabolite with antimicrobial and antiviral properties. Our lab has previously shown that overexpressing ACMSD via adeno-associated virus (AAV) delivery in the alpha-synuclein (α -syn) model of Parkinson's disease (PD) animal model exhibits neuroprotective effects by preventing the loss of dopaminergic neurons in the substantia nigra and limiting motor impairments caused by nigrostriatal denervation. Based on these findings, we predicted that ACMSD would provide neuroprotective effects in the P301S tauopathy model of neurodegenerative disease, a mouse model of frontotemporal dementia (FTD). Specifically, we hypothesized that ACMSD would ameliorate behavioral deficits, including those related to cognitive and emotional processing. We also predicted that ACMSD overexpression would prevent histological indices of pathology, including the expression of hyperphosphorylated tau, gliosis, and neurodegeneration. As previous findings in the literature have denoted sex differences in pathological outcomes of the P301S mouse model (Sun et al., 2020) with males showing more pronounced behavioral deficits and increased hyperphosphorylated tau than females, we hypothesized that ACMSD would show a higher degree of neuroprotection in male P301S mice. P301S and litter/age-matched wild-type controls underwent stereotaxic surgery at two months of age prior to pathological onset to deliver either an AAV-dHS-ACMSD or AAV-dHS-GFP (control) to the dorsal hippocampus. Prior to euthanasia, the mice underwent the Barnes maze test to assess cognitive function focusing on learning and memory recall. Analysis of this assay revealed that male P301S mice treated with ACMSD displayed a trend toward shorter latency in locating the escape hatch during the Barnes Maze test than untreated males, albeit not significant, suggesting a potential enhancement in spatial learning. At eight and a half months, the mice were killed, and their brains harvested. The tissue underwent immunohistochemistry staining for a marker of hyperphosphorylated tau (AT8), markers of gliosis (Iba1 and GFAP), and the pan-neuronal marker (HuC/D) to quantify pathological indices. Preliminary histological analyses show decreased immunoreactivity of AT8 in the hippocampus of P301S mice injected with ACMSD, compared to those injected with GFP control, indicating potential neuroprotective effects by limiting the amount of hyperphosphorylated tau.

Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by impaired motor function including tremor, rigidity, akinesia and postural instability as well as non-motor symptoms including cognitive impairment, depression, and anxiety. Pathological indices of PD consist of protein aggregation of α-synuclein (ɑ-syn), striatal dopaminergic denervation and the loss of dopaminergic neurons in the substantia nigra. While the exact causes of PD remain unknown, substantial evidence suggests that the kynurenine pathway (KP), a pathway upregulated in response to inflammation, is implicated in its pathology. Under normal physiological conditions, the KP catabolizes the amino acid tryptophan to the metabolite 2-amino-3-carboxymuconate-6-semialdehyde (ACMS). ACMS is then spontaneously converted to quinolinic acid (QA), which is an intermediate in the formation of nicotinamide adenine dinucleotide (NAD+), a cofactor in mitochondrial respiration, thus serving as an essential molecule in cellular energy metabolism. QA itself may serve as a contributing factor in PD pathology as this metabolite promotes oxidative stress, mitochondrial dysfunction, excitotoxicity, and positively correlates with increased scores in the Unified Parkinson’s Disease Rating Scale (UPDRS) in motor experiences of daily living (UPDRS II) and motor complications (UPDRS III). ACMS is enzymatically converted to picolinic acid (PA), an iron chelator and anti-viral agent, by 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD), thus limiting the formation of QA and potentially conferring neuroprotective effects. To model Parkinson’s disease, we overexpressed α-synuclein unilaterally in the substantia nigra with an adeno-associated virus (AAV), which leads to dose-dependent neurodegeneration, aggregation of α-syn and motor impairments. This model may therefore serve to examine perturbations of the KP in the context of PD including increased QA/PA expression. We hypothesize that the overexpression of the enzyme ACMSD in the AAV-α-syn model of PD will reduce the degree of neurodegeneration and inflammation and prevent motor decline. Neurodegeneration and neuroinflammation will be quantified histologically, through stereology and densitometry respectively. Observable PD-like symptoms will be quantified using behavioral assessments, particularly the cylinder test and amphetamine induced rotations to assess the degree of motor decline.

Schizophrenia, a debilitating neuropsychiatric disorder, affects 1% of the population. This multifaceted disorder is comprised of positive (hallucinations/psychosis), negative (social withdrawal/anhedonia) and cognitive symptoms. While treatments for schizophrenia have advanced over the past few years, high economic burdens are still conferred to society, totaling more than $34 billion in direct annual costs to the United States of America. Thus, a critical need exists to identify the factors that contribute towards the etiology of schizophrenia. This research aimed to determine the interactions between environmental factors and genetics in the etiology of schizophrenia. Specifically, this research shows that the immediate early gene, early growth response 3 (EGR3), which is upregulated in response to neuronal activity, resides at the center of a biological pathway to confer risk for schizophrenia. While schizophrenia-risk proteins including neuregulin 1 (NRG1) and N-methyl-D-aspartate receptors (NMDAR’s) have been identified upstream of EGR3, the downstream targets of EGR3 remain relatively unknown. This research demonstrates that early growth response 3 regulates the expression of the serotonin 2A-receptor (5HT2AR) in the frontal cortex following the physiologic stimulus, sleep deprivation. This effect is translated to the level of protein as 8 hours of sleep-deprivation results in the upregulation of 5HT2ARs, a target of antipsychotic medications. Additional downstream targets were identified following maximal upregulation of EGR3 through electroconvulsive stimulation (ECS). Both brain-derived neurotrophic factor (BDNF) and its epigenetic regulator, growth arrest DNA-damage-inducible 45 beta (GADD45B) are upregulated one-hour following ECS in the hippocampus and require the presence of EGR3. These proteins play important roles in both cellular proliferation and dendritic structural changes. Next, the effects of ECS on downstream neurobiological processes, hippocampal cellular proliferation and dendritic structural changes were examined. Following ECS, hippocampal cellular proliferationwas increased, and dendritic structural changes were observed in both wild-type and early growth response 3 knock-out (Egr3-/-) mice. Effects in the number of dendritic spines and dendritic complexity following ECS were not found to require EGR3. Collectively, these results demonstrate that neuronal activity leads to the regulation of schizophrenia risk proteins by EGR3 and point to a possible molecular mechanism contributing risk for schizophrenia.