Pathological mechanisms and treatment of sporadic Parkinson’s disease: past, present, and future

The version of record of this article, first published in Journal of Neural Transmission, is available online at Publisher’s website: https://doi.org/10.1007/s00702-024-02788-w.For a special issue, we review studies on the pathogenesis of nigral cell death and the treatment of sporadic Parkinson’s disease (sPD) over the past few decades, with a focus on the studies performed by Prof. Mizuno and our group. Prof. Mizuno proposed the initial concept that mitochondrial function may be impaired in sPD. When working at Jichi Medical School, he found a decrease in complex I of the mitochondrial electron transfer complex in the substantia nigra of patients with Parkinson’s disease (PD) and MPTP models. After moving to Juntendo University as a professor and chairman, he continued to study the mechanisms of cell death in the substantia nigra of patients with sPD. Under his supervision, I studied the relationships between PD and apoptosis, PD and iron involvement, mitochondrial dysfunction and apoptosis, and PD and neuroinflammation. Moving to Kitasato University, we focused on PD and the cytotoxicity of alpha synuclein (αSyn) as well as brain neuropathology. Eventually, I moved to Osaka University, where I continued working on PD and αSyn projects to promote therapeutic research. In this paper, we present the details of these studies in the following order: past, present, and future

Involvement of Mitochondria in Parkinson’s Disease

Choong C.J., Mochizuki H.. Involvement of Mitochondria in Parkinson’s Disease. International Journal of Molecular Sciences 24, 17027 (2023); https://doi.org/10.3390/ijms242317027.Mitochondrial dysregulation, such as mitochondrial complex I deficiency, increased oxidative stress, perturbation of mitochondrial dynamics and mitophagy, has long been implicated in the pathogenesis of PD. Initiating from the observation that mitochondrial toxins cause PD-like symptoms and mitochondrial DNA mutations are associated with increased risk of PD, many mutated genes linked to familial forms of PD, including PRKN, PINK1, DJ-1 and SNCA, have also been found to affect the mitochondrial features. Recent research has uncovered a much more complex involvement of mitochondria in PD. Disruption of mitochondrial quality control coupled with abnormal secretion of mitochondrial contents to dispose damaged organelles may play a role in the pathogenesis of PD. Furthermore, due to its bacterial ancestry, circulating mitochondrial DNAs can function as damage-associated molecular patterns eliciting inflammatory response. In this review, we summarize and discuss the connection between mitochondrial dysfunction and PD, highlighting the molecular triggers of the disease process, the intra- and extracellular roles of mitochondria in PD as well as the therapeutic potential of mitochondrial transplantation

The Functional Network Processing Acute Electrical Itch Stimuli in Humans

The posterior insula (pIns) is a major brain region that receives itch-related signals from the periphery and transfers these signals to broad areas in the brain. Previous brain imaging studies have successfully identified brain regions that respond to itch stimuli. However, it is still unknown which brain regions receive and process itch-related signals from the pIns. Addressing this question is important in identifying key functional networks that process itch. Thus, the present study investigated brain regions with significantly increased functional connectivity with the pIns during itch stimuli with 25 healthy subjects by using functional MRI. Electrical itch stimuli was applied to the left wrist. Similar to previous brain imaging studies, many cortical and subcortical areas were activated by itch stimuli. However, not all of these regions showed significant increments of functional connectivity with the pIns during itch stimuli. While the subjects perceived the itch sensation, functional connectivity was significantly increased between the right pIns and the supplementary motor area (SMA), pre-SMA, anterior midcingulate cortex (aMCC), anterior insula (aIns), secondary somatosensory cortex (SII), and basal ganglia (BG), suggesting that this is a key network in processing itch. In particular, intensity of functional connectivity between the pIns and BG was negatively correlated with itch rating. The functional pIns-BG pathway may play an important role in regulation of subjective itch sensation. This study first identified a key brain network to process itch

Disaggregation Behavior of Amyloid β Fibrils by Anthocyanins Studied by Total-Internal-Reflection-Fluorescence Microscopy Coupled with a Wireless Quartz-Crystal Microbalance Biosensor

Noi K., Ikenaka K., Mochizuki H., et al. Disaggregation Behavior of Amyloid β Fibrils by Anthocyanins Studied by Total-Internal-Reflection-Fluorescence Microscopy Coupled with a Wireless Quartz-Crystal Microbalance Biosensor. Analytical Chemistry, 93(32), 11176-11183, August 17, 2021. Copyright © 2021, American Chemical Society. https://doi.org/10.1021/acs.analchem.1c01720.Amyloid fibrils are formed from various proteins, some of which cause the corresponding neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. It has been reported that many compounds inhibit the formation of amyloid fibrils. Anthocyanins are flavonoid pigments present in fruits and vegetables, which are known to suppress symptoms related with Alzheimer's disease. However, the influence of anthocyanins on the amyloid fibril remains unclear. Here, we succeeded in the direct monitoring of the disaggregation reaction of single amyloid β (Aβ) fibrils by anthocyanins using total-internal-reflection-fluorescence microscopy with a quartz-crystal microbalance (TIRFM-QCM). It is found that the disassembly activity to the Aβ fibrils depends on the number of hydroxyl groups in six-membered ring B of anthocyanin, and only delphinidin-3-galactoside, possessing three hydroxyl groups there, shows high disassembly activity. Our results show the importance of the number of hydroxyl groups and demonstrate the usefulness of TIRFM-QCM as a powerful tool in studying interactions between amyloid fibrils and compounds

Response time differences during hand mental rotation

This study explored gender differences in correct response rates and response times on a task involving left or right arrow selection and another involving the transformation of mental rotation of the hand. We recruited 15 healthy, right-handed men (age 24.5 ± 6.4) and 15 healthy, right-handed women (age 21.3 ± 4.9). For the tasks, we used pictures of left and right arrows and 32 hand pictures (left and right, palm and back) placed in cons (each at 45° from 0° to 315°). Hand and arrow pictures alternated and were shown at random. Participants decided as quickly as possible whether each picture was left or right. To compare the time taken for the transformation of mental rotation of the hand, we subtracted the average arrow response time from that for the left and right hand pictures for each participant. Correct response rates did not differ significantly between men and women or left and right for either arrow or hand pictures. Regardless of gender, the response time was longer for the left arrow picture than right arrow picture. The response time for the hand picture was longest for both men and women for pictures at rotation angles that were most difficult to align with participants’ hands. While there was no difference between men’s responses for left and right hand pictures, the responses of women were longer for left than right hand pictures and also than those of men. These findings suggest that both men and women mainly perform the hand mental rotation task with implicit motor imagery. On the other hand, the gender difference in performance might be explained by the difference in balance with other strategies, such as visual imagery, and by cognitive, neurophysiological, and morphological differences

Driver gene KRAS aggravates cancer-associated stroke outcomes

The incidence of cancer-associated stroke has increased with the prolonged survival times of cancer patients. Recent genetic studies have led to progress in cancer therapeutics, but relationships between oncogenic mutations and stroke remain elusive. Here, we focused on the driver gene KRAS, which is the predominant RAS isoform mutated in multiple cancer types, in cancer associated stroke study. KRASG13D/− and parental human colorectal carcinoma HCT116 cells were inoculated into mice that were then subjected to a photochemically-induced thrombosis model to establish ischemic stroke. We found that cancer inoculation exacerbated neurological deficits after stroke. Moreover, mice inoculated with KRASG13D/− cells showed worse neurological deficits after stroke compared with mice inoculated with parental cells. Stroke promoted tumor growth, and the KRASG13D/− allele enhanced this growth. Brain RNA sequencing analysis and serum ELISA showed that chemokines and cytokines mediating pro-inflammatory responses were upregulated in mice inoculated with KRASG13D/− cells compared with those inoculated with parental cells. STAT3 phosphorylation was promoted following ischemic stroke in the KRASG13D/− group compared with in the parental group, and STAT3 inhibition significantly ameliorated stroke outcomes by mitigating microglia/macrophage polarization. Finally, we compared the prognosis and mortality of colorectal cancer patients with or without stroke onset between 1 January 2007 and 31 December 2020 using a hospital-based cancer registry and found that colorectal cancer patients with stroke onset within 3 months after cancer diagnosis had a worse prognosis. Our work suggests an interplay between KRAS and ischemic stroke that may offer insight into future treatments for cancer-associated stroke.Yan Haomin, Sasaki Tsutomu, Gon Yasufumi, et al. Driver gene KRAS aggravates cancer-associated stroke outcomes. Thrombosis Research 233, 55 (2023); https://doi.org/10.1016/j.thromres.2023.11.015

Positive Correlation between Severity of Blepharospasm and Thalamic Glucose Metabolism

A 43-year-old woman with drug-related blepharospasm was followed up for 22 months. She had undergone etizolam treatment for 19 years for indefinite complaints. We examined her cerebral glucose metabolism 5 times (between days 149 and 688 since presentation), using positron emission tomography, and identified regions of interest in the thalamus, caudate nucleus, putamen, and primary somatosensory area on both sides. The severity of the blepharospasm was evaluated by PET scanning using the Wakakura classification. Sixteen women (mean age 42.4 ± 11.7 years) were examined as normal controls. The thalamic glucose metabolism in our patient was significantly increased on days 149, 212, and 688. The severity of the blepharospasm was positively correlated with the thalamic glucose metabolism, suggesting that the severity of blepharospasms reflects thalamic activity

Time-Lapse Imaging Reveals Symmetric Neurogenic Cell Division of GFAP-Expressing Progenitors for Expansion of Postnatal Dentate Granule Neurons

Granule cells in the hippocampus, a region critical for memory and learning, are generated mainly during the early postnatal period but neurogenesis continues in adulthood. Postnatal neuronal production is carried out by primary progenitors that express glial fibrillary acidic protein (GFAP) and they are assumed to function as stem cells. A central question regarding postnatal dentate neurogenesis is how astrocyte-like progenitors produce neurons. To reveal cell division patterns and the process of neuronal differentiation of astrocyte-like neural progenitors, we performed time-lapse imaging in cultured hippocampal slices from early postnatal transgenic mice with mouse GFAP promoter-controlled enhanced green fluorescent protein (mGFAP-eGFP Tg mice) in combination with a retrovirus carrying a red fluorescent protein gene. Our results showed that the majority of GFAP-eGFP+ progenitor cells that express GFAP, Sox2 and nestin divided symmetrically to produce pairs of GFAP+ cells (45%) or pairs of neuron-committed cells (45%), whereas a minority divided asymmetrically to generate GFAP+ cells and neuron-committed cells (10%). The present results suggest that a substantial number of GFAP-expressing progenitors functions as transient amplifying progenitors, at least in an early postnatal dentate gyrus, although a small population appears to be stem cell-like progenitors. From the present data, we discuss possible cell division patterns of adult GFAP+ progenitors