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Ten new articles of this week on age-related neurodegenerative diseases

Published on: 28 Jan 2023 Viewed: 858

Ageing and Neurodegenerative Diseases (AND) was officially launched on February 8, 2021. The aims of this journal are to report innovative research advances in the cellular and molecular mechanisms underlying the ageing process and age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, etc. The AND editorial office is happy to share the latest research reports or review articles on this field with our readers via this "Weekly News" column.

In this issue, we would like to share the latest articles from Professor Ted M. Dawson, Professor David C. Rubinsztein, Professor Mark Hallett and Professor Heinz Reichmann from the AND Editorial Board.

Title: Blocking microglial activation of reactive astrocytes is neuroprotective in models of Alzheimer’s disease
Authors: Jong-Sung Park, Tae-In Kam, Saebom Lee, Hyejin Park, Yumin Oh, Seung-Hwan Kwon, Jae-Jin Song, Donghoon Kim, Hyunhee Kim, Aanishaa Jhaldiyal, Dong Hee Na, Kang Choon Lee, Eun Ji Park, Martin G. Pomper, Olga Pletnikova, Juan C. Troncoso, Han Seok Ko, Valina L. Dawson, Ted M. Dawson, Seulki Lee
Type: Research Articles from Acta Neuropathologica Communications
Abstract:
Alzheimer's disease (AD) is the most common cause of age-related dementia. Increasing evidence suggests that neuroinflammation mediated by microglia and astrocytes contributes to disease progression and severity in AD and other neurodegenerative disorders. During AD progression, resident microglia undergo proinflammatory activation, resulting in an increased capacity to convert resting astrocytes to reactive astrocytes. Therefore, microglia are a major therapeutic target for AD and blocking microglia-astrocyte activation could limit neurodegeneration in AD. Here we report that NLY01, an engineered exedin-4, glucagon-like peptide-1 receptor (GLP-1R) agonist, selectively blocks β-amyloid (Aβ)-induced activation of microglia through GLP-1R activation and inhibits the formation of reactive astrocytes as well as preserves neurons in AD models. In two transgenic AD mouse models (5xFAD and 3xTg-AD), repeated subcutaneous administration of NLY01 blocked microglia-mediated reactive astrocyte conversion and preserved neuronal viability, resulting in improved spatial learning and memory. Our study indicates that the GLP-1 pathway plays a critical role in microglia-reactive astrocyte associated neuroinflammation in AD and the effects of NLY01 are primarily mediated through a direct action on Aβ-induced GLP-1R+ microglia, contributing to the inhibition of astrocyte reactivity. These results show that targeting upregulated GLP-1R in microglia is a viable therapy for AD and other neurodegenerative disorders.
Access this article: https://doi.org/10.1186/s40478-021-01180-z


Title: AIF3 splicing switch triggers neurodegeneration
Authors: Shuiqiao Liu, Mi Zhou, Zhi Ruan, Yanan Wang, Calvin Chang, Masayuki Sasaki, Veena Rajaram, Andrew Lemoff, Kalyani Nambiar, Jennifer E. Wang, Kimmo J. Hatanpaa, Weibo Luo, Ted M. Dawson, Valina L. Dawson, Yingfei Wang
Type: Articles from Nature Neuroscience
Abstract:
Background
Apoptosis-inducing factor (AIF), as a mitochondrial flavoprotein, plays a fundamental role in mitochondrial bioenergetics that is critical for cell survival and also mediates caspase-independent cell death once it is released from mitochondria and translocated to the nucleus under ischemic stroke or neurodegenerative diseases. Although alternative splicing regulation of AIF has been implicated, it remains unknown which AIF splicing isoform will be induced under pathological conditions and how it impacts mitochondrial functions and neurodegeneration in adult brain.
Methods
AIF splicing induction in brain was determined by multiple approaches including 5′ RACE, Sanger sequencing, splicing-specific PCR assay and bottom-up proteomic analysis. The role of AIF splicing in mitochondria and neurodegeneration was determined by its biochemical properties, cell death analysis, morphological and functional alterations and animal behavior. Three animal models, including loss-of-function harlequin model, gain-of-function AIF3 knockin model and conditional inducible AIF splicing model established using either Cre-loxp recombination or CRISPR/Cas9 techniques, were applied to explore underlying mechanisms of AIF splicing-induced neurodegeneration.
Results
We identified a nature splicing AIF isoform lacking exons 2 and 3 named as AIF3. AIF3 was undetectable under physiological conditions but its expression was increased in mouse and human postmortem brain after stroke. AIF3 splicing in mouse brain caused enlarged ventricles and severe neurodegeneration in the forebrain regions. These AIF3 splicing mice died 2–4 months after birth. AIF3 splicing-triggered neurodegeneration involves both mitochondrial dysfunction and AIF3 nuclear translocation. We showed that AIF3 inhibited NADH oxidase activity, ATP production, oxygen consumption, and mitochondrial biogenesis. In addition, expression of AIF3 significantly increased chromatin condensation and nuclear shrinkage leading to neuronal cell death. However, loss-of-AIF alone in harlequin or gain-of-AIF3 alone in AIF3 knockin mice did not cause robust neurodegeneration as that observed in AIF3 splicing mice.
Conclusions
We identified AIF3 as a disease-inducible isoform and established AIF3 splicing mouse model. The molecular mechanism underlying AIF3 splicing-induced neurodegeneration involves mitochondrial dysfunction and AIF3 nuclear translocation resulting from the synergistic effect of loss-of-AIF and gain-of-AIF3. Our study provides a valuable tool to understand the role of AIF3 splicing in brain and a potential therapeutic target to prevent/delay the progress of neurodegenerative diseases.
Access this article: https://doi.org/10.1186/s13024-021-00442-7


Title: Pathophysiological Changes in the Enteric Nervous System of Rotenone-Exposed Mice as Early Radiological Markers for Parkinson's Disease
Authors: Gabriela Schaffernicht, Qi Shang, Alicia Stievenard, Kai Bötzel, Yanina Dening, Romy Kempe, Magali Toussaint, Daniel Gündel, Mathias Kranz, Heinz Reichmann, Christel Vanbesien-Mailliot, Peter Brust, Marianne Dieterich, Richard H. W. Funk, Ursula Ravens, Francisco Pan-Montojo
Type: Original Research Article from Frontiers in Neurology
Abstract:
Parkinson's disease (PD) is known to involve the peripheral nervous system (PNS) and the enteric nervous system (ENS). Functional changes in PNS and ENS appear early in the course of the disease and are responsible for some of the non-motor symptoms observed in PD patients like constipation, that can precede the appearance of motor symptoms by years. Here we analyzed the effect of the pesticide rotenone, a mitochondrial Complex I inhibitor, on the function and neuronal composition of the ENS by measuring intestinal contractility in a tissue bath and by analyzing related protein expression. Our results show that rotenone changes the normal physiological response of the intestine to carbachol, dopamine and electric field stimulation (EFS). Changes in the reaction to EFS seem to be related to the reduction in the cholinergic input but also related to the noradrenergic input, as suggested by the non-adrenergic non-cholinergic (NANC) reaction to the EFS in rotenone-exposed mice. The magnitude and direction of these alterations varies between intestinal regions and exposure times and is associated with an early up-regulation of dopaminergic, cholinergic and adrenergic receptors and an irregular reduction in the amount of enteric neurons in rotenone-exposed mice. The early appearance of these alterations, that start occurring before the substantia nigra is affected in this mouse model, suggests that these alterations could be also observed in patients before the onset of motor symptoms and makes them ideal potential candidates to be used as radiological markers for the detection of Parkinson's disease in its early stages.
Access this article: https://doi.org/10.3389/fneur.2021.642604


Title: The Phenomenon of Exquisite Motor Control in Tic Disorders and its Pathophysiological Implications
Authors: Christos Ganos, Wolf-Julian Neumann, Kirsten R. Müller-Vahl, Kailash P. Bhatia, Mark Hallett, Patrick Haggard, John Rothwell
Type: Review from Movement Disorders
Abstract:
The unifying characteristic of movement disorders is the phenotypic presentation of abnormal motor outputs, either as isolated phenomena or in association with further clinical, often neuropsychiatric, features. However, the possibility of a movement disorder also characterized by supranormal or enhanced volitional motor control has not received attention. Based on clinical observations and cases collected over a number of years, we here describe the intriguing clinical phenomenon that people with tic disorders are often able to control specific muscle contractions as part of their tic behaviors to a degree that most humans typically cannot. Examples are given in accompanying video documentation. We explore medical literature on this topic and draw analogies with early research of fine motor control physiology in healthy humans. By systematically analyzing the probable sources of this unusual capacity, and focusing on neuroscientific accounts of voluntary motor control, sensory feedback, and the role of motor learning in tic disorders, we provide a novel pathophysiological account explaining both the presence of exquisite control over motor output and that of overall tic behaviors. We finally comment on key questions for future research on the topic and provide concluding remarks on the complex movement disorder of tic behaviors.
Access this article: https://doi.org/10.1002/mds.28557


Title: α-Catenin levels determine direction of YAP/TAZ response to autophagy perturbation
Authors: Mariana Pavel, So Jung Park, Rebecca A. Frake, Sung Min Son, Marco M. Manni, Carla F. Bento, Maurizio Renna, Thomas Ricketts, Fiona M. Menzies, Radu Tanasa, David C. Rubinsztein
Type: Article from Nature Communications
Abstract:
The factors regulating cellular identity are critical for understanding the transition from health to disease and responses to therapies. Recent literature suggests that autophagy compromise may cause opposite effects in different contexts by either activating or inhibiting YAP/TAZ co-transcriptional regulators of the Hippo pathway via unrelated mechanisms. Here, we confirm that autophagy perturbation in different cell types can cause opposite responses in growth-promoting oncogenic YAP/TAZ transcriptional signalling. These apparently contradictory responses can be resolved by a feedback loop where autophagy negatively regulates the levels of α-catenins, LC3-interacting proteins that inhibit YAP/TAZ, which, in turn, positively regulate autophagy. High basal levels of α-catenins enable autophagy induction to positively regulate YAP/TAZ, while low α-catenins cause YAP/TAZ activation upon autophagy inhibition. These data reveal how feedback loops enable post-transcriptional determination of cell identity and how levels of a single intermediary protein can dictate the direction of response to external or internal perturbations.
Access this article: https://doi.org/10.1038/s41467-021-21882-1


Title: Neuroimaging in Functional Neurological Disorder: State of the Field and Research Agenda
Authors: David L. Perez, Timothy R.Nicholson, Ali A. Asadi-Pooya, Indrit Bègue, Matthew Butler, Alan J. Carson, Anthony S.David, QuintonDeeley, IbaiDiez, Mark J. Edwards, Alberto J. Espay, Jeannette M. Gelauff, Mark Hallett, Silvina G. Horovitz, Johannes Jungilligens, Richard A. A. Kanaan, Marina A. J. Tijssen, Kasia Kozlowska, Kathrin LaFaver, W. Curt LaFrance Jr., Sarah C. Lidstone, Ramesh S. Marapin, Carine W. Maurer, Mandana Modirrousta, Antje A. T. S. Reinders, Petr Sojka, Jeffrey P. Staab, Jon Stone, Jerzy P. Szaflarski, Selma Aybek
Type: Review from NeuroImage: Clinical
Abstract:
Functional neurological disorder (FND) was of great interest to early clinical neuroscience leaders. During the 20th century, neurology and psychiatry grew apart – leaving FND a borderland condition. Fortunately, a renaissance has occurred in the last two decades, fostered by increased recognition that FND is prevalent and diagnosed using “rule-in” examination signs. The parallel use of scientific tools to bridge brain structure - function relationships has helped refine an integrated biopsychosocial framework through which to conceptualize FND. In particular, a growing number of quality neuroimaging studies using a variety of methodologies have shed light on the emerging pathophysiology of FND. This renewed scientific interest has occurred in parallel with enhanced interdisciplinary collaborations, as illustrated by new care models combining psychological and physical therapies and the creation of a new multidisciplinary FND society supporting knowledge dissemination in the field. Within this context, this article summarizes the output of the first International FND Neuroimaging Workgroup meeting, held virtually, on June 17th, 2020 to appraise the state of neuroimaging research in the field and to catalyze large-scale collaborations. We first briefly summarize neural circuit models of FND, and then detail the research approaches used to date in FND within core content areas: cohort characterization; control group considerations; task-based functional neuroimaging; resting-state networks; structural neuroimaging; biomarkers of symptom severity and risk of illness; and predictors of treatment response and prognosis. Lastly, we outline a neuroimaging-focused research agenda to elucidate the pathophysiology of FND and aid the development of novel biologically and psychologically-informed treatments.
Access this article: https://doi.org/10.1016/j.nicl.2021.102623


Title: Rotigotine Transdermal Patch for Motor and Non-motor Parkinson’s Disease: A Review of 12 Years’ Clinical Experience
Authors: Vanessa Raeder, Iro Boura, Valentina Leta, Peter Jenner, Heinz Reichmann, Claudia Trenkwalder, Lisa Klingelhoefer, K. Ray Chaudhuri
Type: Review Article from CNS Drugs
Abstract:
Motor and non-motor symptoms (NMS) have a substantial effect on the health-related quality of life (QoL) of patients with Parkinson's disease (PD). Transdermal therapy has emerged as a time-tested practical treatment option, and the rotigotine patch has been used worldwide as an alternative to conventional oral treatment for PD. The efficacy of rotigotine on motor aspects of PD, as well as its safety and tolerability profile, are well-established, whereas its effects on a wide range of NMS have been described and studied but are not widely appreciated. In this review, we present our overall experience with rotigotine and its tolerability and make recommendations for its use in PD and restless legs syndrome, with a specific focus on NMS, underpinned by level 1–4 evidence. We believe that the effective use of the rotigotine transdermal patch can address motor symptoms and a wide range of NMS, improving health-related QoL for patients with PD. More specifically, the positive effects of rotigotine on non-motor fluctuations are also relevant. We also discuss the additional advantages of the transdermal application of rotigotine when oral therapy cannot be used, for instance in acute medical emergencies or nil-by-mouth or pre/post-surgical scenarios. We highlight evidence to support the use of rotigotine in selected cases (in addition to general use for motor benefit) in the context of personalised medicine.
Access this article: https://doi.org/10.1007/s40263-020-00788-4


Title: Autophagy regulation by acetylation—implications for neurodegenerative diseases
Authors: Sung Min Son, So Jung Park, Marian Fernandez-Estevez, David C. Rubinsztein
Type: Review Article from Experimental & Molecular Medicine
Abstract:
Posttranslational modifications of proteins, such as acetylation, are essential for the regulation of diverse physiological processes, including metabolism, development and aging. Autophagy is an evolutionarily conserved catabolic process that involves the highly regulated sequestration of intracytoplasmic contents in double-membrane vesicles called autophagosomes, which are subsequently degraded after fusing with lysosomes. The roles and mechanisms of acetylation in autophagy control have emerged only in the last few years. In this review, we describe key molecular mechanisms by which previously identified acetyltransferases and deacetylases regulate autophagy. We highlight how p300 acetyltransferase controls mTORC1 activity to regulate autophagy under starvation and refeeding conditions in many cell types. Finally, we discuss how altered acetylation may impact various neurodegenerative diseases in which many of the causative proteins are autophagy substrates. These studies highlight some of the complexities that may need to be considered by anyone aiming to perturb acetylation under these conditions.
Access this article: https://doi.org/10.1038/s12276-021-00556-4


Title: LRRK2 Modulates the Exocyst Complex Assembly by Interacting with Sec8
Authors: Milena Fais, Giovanna Sanna, Manuela Galioto, Thi Thanh Duyen Nguyen, Mai Uyên Thi Trần, Paola Sini, Franco Carta, Franco Turrini, Yulan Xiong, Ted M. Dawson, Valina L. Dawson, Claudia Crosio, Ciro Iaccarino
Type: Original Article from Cells
Abstract:
Mutations in LRRK2 play a critical role in both familial and sporadic Parkinson’s disease (PD). Up to date, the role of LRRK2 in PD onset and progression remains largely unknown. However, experimental evidence highlights a critical role of LRRK2 in the control of vesicle trafficking, likely by Rab phosphorylation, that in turn may regulate different aspects of neuronal physiology. Here we show that LRRK2 interacts with Sec8, one of eight subunits of the exocyst complex. The exocyst complex is an evolutionarily conserved multisubunit protein complex mainly involved in tethering secretory vesicles to the plasma membrane and implicated in the regulation of multiple biological processes modulated by vesicle trafficking. Interestingly, Rabs and exocyst complex belong to the same protein network. Our experimental evidence indicates that LRRK2 kinase activity or the presence of the LRRK2 kinase domain regulate the assembly of exocyst subunits and that the over-expression of Sec8 significantly rescues the LRRK2 G2019S mutant pathological effect. Our findings strongly suggest an interesting molecular mechanism by which LRRK2 could modulate vesicle trafficking and may have important implications to decode the complex role that LRRK2 plays in neuronal physiology.
Access this article: https://doi.org/10.3390/cells10020203


Title: Assessment of real life eating difficulties in Parkinson’s disease patients by measuring plate to mouth movement elongation with inertial sensors
Authors: Konstantinos Kyritsis, Petter Fagerberg, Ioannis Ioakimidis, K. Ray Chaudhuri, Heinz Reichmann, Lisa Klingelhoefer, Anastasios Delopoulos
Type: Article from Scientific Reports
Abstract:
Parkinson’s disease (PD) is a neurodegenerative disorder with both motor and non-motor symptoms. Despite the progressive nature of PD, early diagnosis, tracking the disease’s natural history and measuring the drug response are factors that play a major role in determining the quality of life of the affected individual. Apart from the common motor symptoms, i.e., tremor at rest, rigidity and bradykinesia, studies suggest that PD is associated with disturbances in eating behavior and energy intake. Specifically, PD is associated with drug-induced impulsive eating disorders such as binge eating, appetite-related non-motor issues such as weight loss and/or gain as well as dysphagia—factors that correlate with difficulties in completing day-to-day eating-related tasks. In this work we introduce Plate-to-Mouth (PtM), an indicator that relates with the time spent for the hand operating the utensil to transfer a quantity of food from the plate into the mouth during the course of a meal. We propose a two-step approach towards the objective calculation of PtM. Initially, we use the 3D acceleration and orientation velocity signals from an off-the-shelf smartwatch to detect the bite moments and upwards wrist micromovements that occur during a meal session. Afterwards, we process the upwards hand micromovements that appear prior to every detected bite during the meal in order to estimate the bite’s PtM duration. Finally, we use a density-based scheme to estimate the PtM durations distribution and form the in-meal eating behavior profile of the subject. In the results section, we provide validation for every step of the process independently, as well as showcase our findings using a total of three datasets, one collected in a controlled clinical setting using standardized meals (with a total of 28 meal sessions from 7 Healthy Controls (HC) and 21 PD patients) and two collected in-the-wild under free living conditions (37 meals from 4 HC/10 PD patients and 629 meals from 3 HC/3 PD patients, respectively). Experimental results reveal an Area Under the Curve (AUC) of 0.748 for the clinical dataset and 0.775/1.000 for the in-the-wild datasets towards the classification of in-meal eating behavior profiles to the PD or HC group. This is the first work that attempts to use wearable Inertial Measurement Unit (IMU) sensor data, collected both in clinical and in-the-wild settings, towards the extraction of an objective eating behavior indicator for PD.
Access this article: https://doi.org/10.1038/s41598-020-80394-y

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