JM Dijkstra

Treatment with levodopa, a precursor of dopamine (DA), to compensate for the loss of endogenous DA in Parkinson's disease (PD), has been a success story for over 50 years. However, in late stages of PD, the progressive degeneration of dopaminergic neurons and the ongoing reduction in endogenous DA concentrations make it increasingly difficult to maintain normal-like DA function. Typically, in late PD, higher doses of levodopa are required, and the fluctuations in striatal DA concentrations-reflecting the timing pattern of levodopa administrations-become more pronounced. These DA fluctuations can include highs that induce involuntary movements (levodopa-induced dyskinesia, LID) or lows that result in insufficient suppression of PD symptoms ("OFF" phases). The enhanced fluctuations primarily arise from the loss of DA buffering capacity, resulting from the degeneration of DA neurons, and an increased reliance on levodopa-derived DA release as a "false neurotransmitter" by serotonergic neurons. In many patients, the LID and OFF-phases can be alleviated by modifying the levodopa therapy to provide a more continuous delivery or by using additional medications, such as monoamine oxidase-B (MAO-B) inhibitors, amantadine, or dopaminergic receptor agonists. Understanding the challenges faced by levodopa therapy also requires considering that the PD striatum is characterized not only by the loss of DA neurons but also by neuroplastic adaptations and PD-induced degenerations of other neural populations. This review provides a broad overview on the use of levodopa in treating PD, with a focus on the underlying science of the challenges encountered in late stages of the disease.

BACKGROUND: α-Synuclein (α-syn) seed amplification assays (SAAs) have shown remarkable potential in diagnosing Parkinson's disease (PD). Using data from the Parkinson's Progression Markers Initiative (PPMI) cohort, we aimed to test whether baseline α-syn seeding activity was associated with disease progression in sporadic PD, LRRK2-associated PD (LRRK2 PD), and GBA-associated PD (GBA PD). METHODS: We analyzed 7 years of motor, non-motor, and cognitive assessments and 5 years of dopamine transporter imaging along with baseline α-syn SAA results from 564 PPMI participants (n=332 sporadic PD, 162 LRRK2 PD, and 70 GBA PD) using linear mixed-effects models, adjusted for potential confounders, to test whether baseline α-syn SAA positivity (n=315 sporadic PD, 111 LRRK2 PD, and 66 GBA PD) was associated with PD progression. RESULTS: While non-statistically significant, there was a trend towards faster motor decline in participants with α-syn SAA positive LRRK2 PD compared to those with α-syn SAA negative LRRK2 PD (MDS-UPDRS III points per year: 2.39 (95% confidence interval: 1.86 - 2.92) vs. 1.76 (0.93 - 2.60); difference=0.63 (-0.29 - 1.55, p=0.18). There was no difference in motor decline between α-syn SAA positive and α-syn SAA negative participants with sporadic PD (2.46 (2.20 - 2.72) vs. 2.39 (1.36 - 3.42); difference=0.07 (-0.99 - 1.12), p=0.90) or GBA PD (2.67 (1.91 - 3.44) vs. 2.40 (-0.18 - 4.99); difference=0.27 (-2.42 - 2.96), p=0.84). No statistically significant differences were seen in the progression of non-motor symptoms, cognition, or DAT imaging. CONCLUSIONS: We found no statistically significant associations between baseline α-syn seeding activity and PD progression among manifest patients in the PPMI cohort. Future studies are needed to further investigate relationships among baseline α-syn seeding activity, disease heterogeneity, disease stage, and PD progression.

Parvalbumins are the main source of food allergies in fish meat, with each fish possessing multiple different parvalbumins. The naming convention of these allergens in terms of allergen codes (numbers) is species-specific. Allergen codes for parvalbumin isoallergens and allergen variants are based on sequence identities relative to the first parvalbumin allergen discovered in that particular species. This means that parvalbumins with similar allergen codes, such as catfish Pan h 1.0201 and redfish Seb m 1.0201, are not necessarily the most similar proteins, or encoded by the same gene. Here, we aim to elucidate the molecular basis of parvalbumins. We explain the complicated genetics of fish parvalbumins in an accessible manner for fish allergen researchers. Teleost or modern bony fish, which include most commercial fish species, have varying numbers of up to 22 parvalbumin genes. All have derived from ten parvalbumin genes in their common ancestor. We have named these ten genes "parvalbumin 1-to-10" (PVALB1-to-PVALB10), building on earlier nomenclature established for zebrafish. For duplicated genes, we use variant names such as, for example, "PVALB2A and PVALB2B". As illustrative examples of our gene identification system, we systematically analyze all parvalbumin genes in two common allergy-inducing species in Japan: red seabream (Pagrus major) and chum salmon (Oncorhynchus keta). We also provide gene identifications for known parvalbumin allergens in various fish species.

The core pathological event in Parkinson's disease (PD) is the specific dying of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). The reasons why SNc DA neurons are especially vulnerable and why idiopathic PD has only been found in humans are still puzzling. The two main underlying factors of SNc DA neuron vulnerability appear related to high DA production, namely (i) the toxic effects of cytoplasmic DA metabolism and (ii) continuous cytosolic Ca2+ oscillations in the absence of the Ca2+-buffer protein calbindin. Both factors cause oxidative stress by producing highly reactive quinones and increasing intra-mitochondrial Ca2+ concentrations, respectively. High DA expression in human SNc DA neuron cell bodies is suggested by the abundant presence of the DA-derived pigment neuromelanin, which is not found in such abundance in other species and has been associated with toxicity at higher levels. The oxidative stress created by their DA production system, despite the fact that the SN does not use unusually high amounts of energy, explains why SNc DA neurons are sensitive to various genetic and environmental factors that create mitochondrial damage and thereby promote PD. Aging increases multiple risk factors for PD, and, to a large extent, PD is accelerated aging. To prevent PD neurodegeneration, possible approaches that are discussed here are (1) reducing cytoplasmic DA accumulation, (2) blocking cytoplasmic Ca2+ oscillations, and (3) providing bioenergetic support.

Distinguished Professor Emeritus Tsuneko Okazaki is a hero of science. Together with her late husband, Professor Reiji Okazaki, she discovered that DNA replication involves the discontinuous synthesis of the DNA lagging strand by intermediates of, what is now called, "Okazaki fragments." She has been a pioneer for women in science and, in 1983, became the first female full Professor at Nagoya University. From 1997 to 2012, she was a full Professor and later a Visiting Professor at Fujita Health University, and this review zooms in on that period. Besides a summary of her career, this article also includes personal memories of researchers who worked with Professor Okazaki.