Purpose Of Review: Neuroinflammation is an important mediator of the pathogenesis of disease in amyotrophic lateral sclerosis (ALS). Genetic mutations such as C9orf72 have begun to define the numerous cell autonomous pathways that initiate motor neuron injury. Yet, it is the signalling to surrounding glia and peripherally derived immune cells that initiates the noncell autonomous inflammatory process and promotes self-propagating motor neuron cell death. The purpose of this review is to explore the systemic immune/inflammatory contributions to the pathogenesis of ALS: what are the peripheral pro-inflammatory signatures, what initiates their presence and do they represent potential therapeutic targets.
Recent Findings: In ALS, motor neuron cell death is initiated by multiple cell autonomous pathways leading to misfolded proteins, oxidative stress, altered mitochondria, impaired autophagy and altered RNA metabolism, which collectively promote noncell autonomous inflammatory reactivity. The resulting disease is characterized by activated microglia and astrocytes as well as peripherally derived pro-inflammatory innate and adaptive immune cells. In this unrelenting disorder, circulating blood monocytes and natural killer cells are pro-inflammatory. Furthermore, regulatory T lymphocytes are dysfunctional, and pro-inflammatory cytokines and acute phase proteins are elevated.
Summary: The collective dysregulation of cells and cytokines in patients with ALS accurately reflect increased disease burdens, more rapid progression rates and reduced survival times, reinforcing the concept of ALS as a disorder with extensive systemic pro-inflammatory responses. These increased systemic pro-inflammatory immune constituents provide potentially meaningful therapeutic targets.
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http://dx.doi.org/10.1097/WCO.0000000000000983 | DOI Listing |
Cell-type-specific activation of parvalbumin (PV)-expressing neurons in the external globus pallidus (GPe) through optogenetics has shown promise in facilitating long-lasting movement dysfunction recovery in mice with Parkinson's disease. However, its translational potential is hindered by adverse effects stemming from the invasive implantation of optical fibers into the brain. In this study, we have developed a non-invasive optogenetics approach, utilizing focused ultrasound-triggered mechanoluminescent nanotransducers to enable remote photon delivery deep in the brain for genetically targeted neuromodulation.
View Article and Find Full Text PDFNeurons require high amounts energy, and mitochondria help to fulfill this requirement. Dysfunc-tional mitochondria trigger problems in various neuronal tasks. Using the neuromuscular junction (NMJ) as a model synapse, we previously reported that Mitochondrial Complex I (MCI) subunits were required for maintaining NMJ function and growth.
View Article and Find Full Text PDFLymphocyte activation gene 3 (LAG3) is a key receptor involved in the propagation of pathological proteins in Parkinson's disease (PD). This study investigates the role of neuronal LAG3 in mediating the binding, uptake, and propagation of α-synuclein (αSyn) preformed fibrils (PFFs). Using neuronal LAG3 conditional knockout mice and human induced pluripotent stem cells-derived dopaminergic (DA) neurons, we demonstrate that LAG3 expression is critical for pathogenic αSyn propagation.
View Article and Find Full Text PDFParkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, primarily due to the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Factors contributing to this neuronal degeneration include mitochondrial dysfunction, oxidative stress, and neuronal excitotoxicity. Despite extensive research, the exact etiology of PD remains unclear, with both genetic and environmental factors playing significant roles.
View Article and Find Full Text PDFJ Neurochem
January 2025
Department of Pathology, School of Veterinary Medicine, University of São Paulo, Sao Paulo, Brazil.
Autism spectrum disorder (ASD) is a complex developmental disorder characterized by several behavioral impairments, especially in socialization, communication, and the occurrence of stereotyped behaviors. In rats, prenatal exposure to valproic acid (VPA) induces autistic-like behaviors. Previous studies by our group have suggested that the autistic-like phenotype is possibly related to dopaminergic system modulation because tyrosine hydroxylase (TH) expression was affected.
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