Our staff editors continue to share brilliant, thoughtful, and meaningful topics and articles in the recommended series.
This week, we would like to share several latest articles from our Editorial Board Member.
Title: Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson’s disease
Authors: Nikhil Panicker, Tae-In Kam, Hu Wang, Stewart Neifert, Shih-Ching Chou, Manoj Kumar, Saurav Brahmachari, Aanishaa Jhaldiyal, Jared T. Hinkle, Fatih Akkentli, Xiaobo Mao, Enquan Xu, Senthilkumar S. Karuppagounder, Eric T. Hsu, Sung-Ung Kang, Olga Pletnikova, Juan Troncoso, Valina L. Dawson, Ted M. Dawson
Type: Research Article
●NLRP3 is a parkin polyubiquitination substrate
●Loss of parkin primes and activates the NLRP3 inflammasome in dopamine neurons
●Accumulation of PARIS due to loss of parkin drives NLRP3 inflammasome activation
●Inhibiting neuronal NLRP3 inflammasome assembly prevents neurodegeneration in PD
Parkinson’s disease (PD) is mediated, in part, by intraneuronal accumulation of α-synuclein aggregates andsubsequent death of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc). Microglial hyperactivation of the NOD-like receptor protein 3 (NLRP3) inflammasome has been well-documented in various neurodegenerative diseases, including PD. We show here that loss of parkin activity in mouse and human DA neurons results in spontaneous neuronal NLRP3 inflammasome assembly, leading to DA neuron death. Parkin normally inhibits inflammasome priming by ubiquitinating and targeting NLRP3 for proteasomal degradation. Loss of parkin activity also contributes to the assembly of an active NLRP3 inflammasome complex via mitochondrial-derived reactive oxygen species (mitoROS) generation through the accumulation of another parkin ubiquitination substrate, ZNF746/PARIS. Inhibition of neuronal NLRP3 inflammasome assembly prevents degeneration of DA neurons in familial and sporadic PD models. Strategies aimed at limiting neuronal NLRP3 inflammasome activation hold promise as a disease-modifying therapy for PD.
Access this article: https://doi.org/10.1016/j.neuron.2022.05.009
Title: Diagnosis and classification of blepharospasm: Recommendations based on empirical evidence
Authors: Gamze Kilic-Berkmen, Giovanni Defazio, Mark Hallett, Alfredo Berardelli, Gina Ferrazzano, Daniele Belvisi, Christine Klein, Tobias Bäumer, Anne Weissbach, Joel S. Perlmutter, Jeanne Feuerstein, H.A. Jinnah
Type: Research Ariticle
●Blepharospasm (BSP) is one of the most common subtypes of dystonia.
●Current guidelines for diagnosis and classification are ambiguous.
●These ambiguities are interpreted differently by movement disorder specialists.
●Here we provide more specific recommendations for diagnosis and classification.
Blepharospasm is one of the most common subtypes of dystonia, and often spreads to other body regions. Despite published guidelines, the approach to diagnosis and classification of affected body regions varies among clinicians.
To delineate the clinical features used by movement disorder specialists in the diagnosis and classification of blepharospasm according to body regions affected, and to develop recommendations for a more consistent approach.
Cross-sectional data for subjects diagnosed with all types of isolated dystonia were acquired from the Dystonia Coalition, an international, multicenter collaborative research network. Data were evaluated to determine how examinations recorded by movement disorder specialists were used to classify blepharospasm as focal, segmental, or multifocal.
Among all 3222 participants with isolated dystonia, 210 (6.5%) had a diagnosis of focal blepharospasm. Among these 210 participants, 34 (16.2%) had dystonia outside of upper face region. Factors such as dystonia severity across different body regions and number of body regions affected influenced the classification of blepharospasm as focal, segmental, or multifocal.
Although focal blepharospasm is the second most common type of dystonia, a high percentage of individuals given this diagnosis had dystonia outside of the eye/upper face region. These findings are not consistent with existing guidelines for the diagnosis and classification of focal blepharospasm, and point to the need for more specific guidelines for more consistent application of existing recommendations for diagnosis and classification.
Access this article: https://doi.org/10.1016/j.jns.2022.120319
Title: The Association Between Race and Place of Death Among Persons With Dementia
Authors: Inbal Mayan, Kristine Yaffe, Jennifer James, Lauren J. Hunt
Type: Brief Report
Little is known about racial differences in place of death for persons with dementia (PWD), who may be especially vulnerable to receiving care at end of life that is not concordant with their goals or that places higher burden on caregivers.
To determine if there are racial and ethnic differences in place of death among PWD.
We analyzed data from the nationally representative National Health and Aging Trends study. Participants were included if they had probable dementia as defined by a previously validated algorithm and died between 2012 and 2020. Race and ethnicity were self-reported. Place of death was obtained from post-mortem interviews with bereaved caregivers.
The sample included 993 decedents with dementia (81.4% white; 11.0% black, 7.6% hispanic). A higher percentage of black and hispanic decedents died in the hospital (30.3% and 32.8%, respectively) compared to white decedents (19.0%). A higher percentage of white decedents died in the nursing home (31.0%) than black (22.4%) or hispanic decedents (15.0%) In adjusted analyses, black decedents had a higher odds of hospital death (AOR 1.50; 95% CI 1.01, 2.24) compared to white decedents, with similar trends found for hispanic decedents.
We found racial and ethnic differences in location of death for PWD, with black and hispanic PWD more likely to die in the hospital compared to white PWD. More research is needed to determine if the differences found represent goal concordant care or rather lack of access to high quality of care at the end of life.
Access this article: https://doi.org/10.1016/j.jpainsymman.2022.05.010
Title: Selective expression of neurodegenerative diseases-related mutant p150Glued in midbrain dopaminergic neurons causes progressive degeneration of nigrostriatal pathway
Authors: Jia Yu, Carmelo Sgobio, Xuan Yang, Yu Peng, Xi Chen, Lixin Sun, Hoon Shim, Huaibin Cai
Type: Original Artical
Aim: Missense mutations of dynactin subunit p150Glued have been associated with multiple neurodegenerative diseases, including Perry syndrome, characterized by inherited parkinsonism, depression, weight loss, and hypoventilation. The current study investigated how the pathogenic mutant p150Glued affects the integrity and function of the nigrostriatal dopaminergic (DA) pathway in vivo.
Methods: Using a tetracycline-controlled transcriptional regulation system, transgenic mouse models were generated with selective overexpression of wild-type, motor neuron disease-related G59S mutant, or Perry syndrome-related G71R mutant human p150Glued in midbrain DA neurons. A series of behavioral, neuropathological, neurochemical, electrochemical, and biochemical studies were performed on the mice to examine and compare the pathogenic impact of the two mutant p150Glued on the survival and function of midbrain DA neurons.
Results: Compared with non-transgenic control mice, transgenic mice overexpressing wild-type human p150Glued showed neither motor phenotypes nor pathological, functional, or biochemical abnormalities of the nigrostriatal DA pathway. Transgenic mice overexpressing G59S mutant p150Glued displayed weight loss, motor deficits, early-onset defects in dopamine transmission, and early-onset loss of DA neurons and axons. Transgenic mice overexpressing G71R p150Glued mutant exhibited hyperactivities, impaired motor coordination, early-onset dysfunction of dopamine uptake, and late-onset loss of DA neurons and axons. In addition, overexpression of either G59S or G71R mutant p150Glued in midbrain DA neurons preferentially downregulated the expression of dopamine transporter at dopaminergic axon terminals. Furthermore, G59S mutant p150Glued rather than G71R mutant p150Glued formed aggregates in midbrain DA neurons in vivo, and the aggregates trapped dynein/dynactin, co-localized with lysosomes, and upregulated ubiquitination.
Conclusion: These findings demonstrate that selective expression of either G59S or G71R mutant p150Glued in mouse midbrain DA neurons leads to progressive degeneration of the nigrostriatal DA pathway and indicate that G59S and G71R mutant p150Glued exhibit differential pathogenic impact on the survival and function of midbrain DA neurons in vivo.
Access this article: https://ageneudisjournal.com/article/view/4832
Title: Linking circadian rhythms to microbiome-gut-brain axis in aging-associated neurodegenerative diseases
Authors: Wai-Yin Cheng, Yuen-Shan Ho, Raymond Chuen-Chung Chang
Type: Review Article
●Disruption of circadian gene affects sleep-wake cycle and neurodegeneration.
●Gut microbiota modulates endocrine/immune systems affecting neurodegeneration.
●Bidirectional relationship between gut microbiota and circadian rhythms.
●Bidirectional relationship between circadian rhythms and neuronal activities.
●Modulation of gut microbiota as therapeutic approach of neurodegeneration.
Emerging evidence suggests that both disruption of circadian rhythms and gut dysbiosis are closely related to aging-associated neurodegenerative diseases. Over the last decade, the microbiota-gut-brain axis has been an emerging field and revolutionized studies in pathology, diagnosis, and treatment of neurological disorders. Crosstalk between the brain and gut microbiota can be accomplished via the endocrine, immune, and nervous system. Recent studies have shown that the composition and diurnal oscillation of gut microbiota are influenced by host circadian rhythms. This provides a new perspective for investigating the microbiome-gut-brain axis. We aim to review current understanding and research on the dynamic interaction between circadian rhythms and the microbiome-gut-brain axis. Furthermore, we will address the possible neurodegenerative disease contribution through circadian rhythms and microbiome-gut-brain axis crosstalk.
Access this article: https://doi.org/10.1016/j.arr.2022.101620