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Current Opinion in Neurology Jun 2024Anti-IgLON5 disease is characterized by a distinctive sleep disorder, associated with a heterogeneous spectrum of neurological symptoms. Initial autopsies showed a novel... (Review)
Review
PURPOSE OF REVIEW
Anti-IgLON5 disease is characterized by a distinctive sleep disorder, associated with a heterogeneous spectrum of neurological symptoms. Initial autopsies showed a novel neuronal tauopathy predominantly located in the tegmentum of the brainstem. Recently, new diagnostic red flags, biomarkers predictors of response to immunotherapy, and novel insights into the autoimmune pathogenesis of the disease have been reported.
RECENT FINDINGS
Patients with diagnosis of neurodegenerative dementia, progressive supranuclear palsy (PSP) or with motor-neuron disease (MND)-like syndrome have been reported to have IgLON5 antibodies, which are the hallmark of anti-IgLON5 disease. Second, low levels of neurofilament light chain in serum and cerebrospinal fluid of patients at disease onset could be a predictor of immunotherapy response. Recent neuropathological studies indicate that the neuronal tau deposits occur late in the course of the disease. Moreover, IgLON5 antibodies induce cytoskeletal changes in cultured hippocampal neurons suggesting that the tauopathy could be secondary of the IgLON5 antibody effects.
SUMMARY
Anti-IgLON5 disease can mimic and should be considered in atypical presentations of MND, neurodegenerative dementia and PSP. Neurofilament light chain levels seem promising biomarker for disease prognosis. Finally, the neuropathological and in vitro experimental studies strengthen the autoimmune hypothesis of the disease.
Topics: Animals; Humans; Autoantibodies; Biomarkers; Cell Adhesion Molecules, Neuronal; Neurofilament Proteins; Supranuclear Palsy, Progressive; Motor Neuron Disease; Neurodegenerative Diseases
PubMed: 38563128
DOI: 10.1097/WCO.0000000000001271 -
Journal of Clinical Medicine Jan 2024Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder which causes the selective deterioration of the upper motor neurons (UMNs), sparing the lower motor... (Review)
Review
Primary lateral sclerosis (PLS) is a rare neurodegenerative disorder which causes the selective deterioration of the upper motor neurons (UMNs), sparing the lower motor neuron (LMN) system. The clinical course is defined by a progressive motor disability due to muscle spasticity which typically involves lower extremities and bulbar muscles. Although classically considered a sporadic disease, some familiar cases and possible causative genes have been reported. Despite it having been recognized as a rare but distinct entity, whether it actually represents an extreme end of the motor neuron diseases continuum is still an open issue. The main knowledge gap is the lack of specific biomarkers to improve the clinical diagnostic accuracy. Indeed, the diagnostic imprecision, together with some uncertainty about overlap with UMN-predominant ALS and Hereditary Spastic Paraplegia (HSP), has become an obstacle to the development of specific therapeutic trials. In this study, we provided a comprehensive analysis of the existing literature, including neuropathological, clinical, neuroimaging, and neurophysiological features of the disease, and highlighting the controversies still unsolved in the differential diagnoses and the current diagnostic criteria. We also discussed the current knowledge gaps still present in both diagnostic and therapeutic fields when approaching this rare condition.
PubMed: 38276084
DOI: 10.3390/jcm13020578 -
Communications Biology Nov 2023Beyond motor neuron degeneration, homozygous mutations in the survival motor neuron 1 (SMN1) gene cause multiorgan and metabolic defects in patients with spinal muscular...
Beyond motor neuron degeneration, homozygous mutations in the survival motor neuron 1 (SMN1) gene cause multiorgan and metabolic defects in patients with spinal muscular atrophy (SMA). However, the precise biochemical features of these alterations and the age of onset in the brain and peripheral organs remain unclear. Using untargeted NMR-based metabolomics in SMA mice, we identify cerebral and hepatic abnormalities related to energy homeostasis pathways and amino acid metabolism, emerging already at postnatal day 3 (P3) in the liver. Through HPLC, we find that SMN deficiency induces a drop in cerebral norepinephrine levels in overt symptomatic SMA mice at P11, affecting the mRNA and protein expression of key genes regulating monoamine metabolism, including aromatic L-amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DβH) and monoamine oxidase A (MAO-A). In support of the translational value of our preclinical observations, we also discovered that SMN upregulation increases cerebrospinal fluid norepinephrine concentration in Nusinersen-treated SMA1 patients. Our findings highlight a previously unrecognized harmful influence of low SMN levels on the expression of critical enzymes involved in monoamine metabolism, suggesting that SMN-inducing therapies may modulate catecholamine neurotransmission. These results may also be relevant for setting therapeutic approaches to counteract peripheral metabolic defects in SMA.
Topics: Animals; Humans; Mice; Amino Acids; Motor Neurons; Muscular Atrophy, Spinal; Neurotransmitter Agents; Norepinephrine; Survival of Motor Neuron 1 Protein
PubMed: 37957344
DOI: 10.1038/s42003-023-05543-1 -
International Journal of Molecular... Oct 2023Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, characterized in its typical presentation by a combination of lower and upper motor neuron symptoms,... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, characterized in its typical presentation by a combination of lower and upper motor neuron symptoms, with a progressive course and fatal outcome. Due to increased recognition of the non-motor symptoms, it is currently considered a multisystem disorder with great heterogeneity, regarding genetical, clinical, and neuropathological features. Often underestimated, autonomic signs and symptoms have been described in patients with ALS, and various method analyses have been used to assess autonomic nervous system involvement. The aim of this paper is to offer a narrative literature review on autonomic disturbances in ALS, based on the scarce data available to date.
Topics: Humans; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Motor Neurons; Primary Dysautonomias
PubMed: 37834374
DOI: 10.3390/ijms241914927 -
Neurobiology of Disease Aug 2023The progressive neurodegenerative disease amyotrophic lateral sclerosis (ALS) is caused by a decline in motor neuron function, resulting in worsened motor impairments,...
The progressive neurodegenerative disease amyotrophic lateral sclerosis (ALS) is caused by a decline in motor neuron function, resulting in worsened motor impairments, malnutrition, respiratory failure and mortality, and there is a lack of effective clinical treatments. The exact mechanism of motor neuronal degeneration remains unclear. Previously, we reported that ferroptosis, which is characterized by the accumulation of lipid peroxide and glutathione depletion in an iron-dependent manner, contributed to motor neuronal death in ALS cell models with the hSOD1 (human Cu/Zn-superoxide dismutase) gene mutation. In this study, we further explored the role of ferroptosis in motor neurons and its regulation in mutant hSOD1 cell and mouse models. Our results showed that ferroptosis was activated in hSOD1 NSC-34 cells and mouse models, which was accompanied by decreased nuclear retention of nuclear factor erythroid 2-related factor 2 (NRF2) and downregulation of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) levels. Moreover, RTA-408, an NRF2 activator, inhibited ferroptosis in hSOD1 NSC-34 cells by upregulating the protein expression of SLC7A11 and GPX4. Moreover, hSOD1 mice treated with RTA-408 showed obvious improvements in body weight and motor function. Our study demonstrated that ferroptosis contributed to the toxicity of motor neurons and that activating NRF2 could alleviate neuronal degeneration in ALS with the hSOD1 mutation.
Topics: Animals; Humans; Mice; Amyotrophic Lateral Sclerosis; Disease Models, Animal; Ferroptosis; Mice, Transgenic; Motor Neurons; Mutation; Neurodegenerative Diseases; Neuroprotection; NF-E2-Related Factor 2; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 37352984
DOI: 10.1016/j.nbd.2023.106210 -
Current Opinion in Neurology Aug 2023Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease of the motor system due to the selective and progressive degeneration of both upper and... (Review)
Review
PURPOSE OF THE REVIEW
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease of the motor system due to the selective and progressive degeneration of both upper and lower motor neurons. Disturbances in energy homeostasis were repeatedly associated with the ALS pathogenesis and appear early during the disease process. In this review, we highlight recent work demonstrating the crucial role of energy metabolism in ALS and discuss its potential clinical relevance.
RECENT FINDINGS
The alteration of various metabolic pathways contributes to the heterogeneity of the clinical phenotype of ALS. Recent work showed that different ALS mutations selectively impact these pathways and translate to the disease phenotypes in patients and disease models. Strikingly, a growing number of studies point towards an early, even presymptomatic, contribution of abnormal energy homeostasis to the ALS pathogenesis. Advances in metabolomics generated valuable tools to study altered metabolic pathways, to test their therapeutic potential, and to develop personalized medicine. Importantly, recent preclinical studies and clinical trials demonstrated that targeting energy metabolism is a promising therapeutic approach.
SUMMARY
Abnormal energy metabolism is a key player in ALS pathogenesis, emerging as a source of potential disease biomarkers and therapeutic targets.
Topics: Humans; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Motor Neurons; Energy Metabolism; Precision Medicine
PubMed: 37338894
DOI: 10.1097/WCO.0000000000001164 -
Journal of Cachexia, Sarcopenia and... Oct 2023The functional deterioration and loss of motor neurons are tightly associated with degenerative motor neuron diseases and aging-related muscle wasting. Motor neuron...
BACKGROUND
The functional deterioration and loss of motor neurons are tightly associated with degenerative motor neuron diseases and aging-related muscle wasting. Motor neuron diseases or aging-related muscle wasting in turn contribute to increased risk of adverse health outcomes in the elderly. Cdon (cell adhesion molecule-downregulated oncogene) belongs to the immunoglobulin superfamily of cell adhesion molecule and plays essential roles in multiple signalling pathways, including sonic hedgehog (Shh), netrin, and cadherin-mediated signalling. Cdon as a Shh coreceptor plays a critical role in motor neuron specification during embryonic development. However, its role in adult motor neuron function is unknown.
METHODS
Hb9-Cre recombinase-driven motor neuron-specific Cdon deficient mice (mnKO) and a compound mutant mice (mnKO::SOD1 ) were generated to investigate the role of Cdon in motor neuron degeneration. Motor neuron regeneration was examined by using a sciatic nerve crush injury model. To investigate the phenotype, physical activity, compound muscle action potential, immunostaining, and transmission electron microscopy were carried out. In the mechanism study, RNA sequencing and RNA/protein analyses were employed.
RESULTS
Mice lacking Cdon in motor neurons exhibited middle age onset lethality and aging-related decline in motor function. In the sciatic nerve crush injury model, mnKO mice exhibited an impairment in motor function recovery evident by prolonged compound muscle action potential duration (4.63 ± 0.35 vs. 3.93 ± 0.22 s for f/f, P < 0.01) and physical activity. Consistently, neuromuscular junctions of mnKO muscles were incompletely occupied (49.79 ± 5.74 vs. 79.39 ± 3.77% fully occupied neuromuscular junctions for f/f, P < 0.0001), suggesting an impaired reinnervation. The transmission electron microscopy analysis revealed that mnKO sciatic nerves had smaller axon diameter (0.88 ± 0.13 vs. 1.43 ± 0.48 μm for f/f, P < 0.0001) and myelination defects. RNA sequencing of mnKO lumbar spinal cords showed alteration in genes related to neurogenesis, inflammation and cell death. Among the altered genes, ErbB4 and FgfR expressions were significantly altered in mnKO as well as in Cdon-depleted NSC34 motor neuron cells. Consistently, Cdon-depleted NSC34 cells exhibited elevated levels of cleaved Caspase3 and γH2AX proteins, as well as Bax transcription. Cdon-depleted NSC34 cells also exhibited impaired activation of Akt in response to neuregulin-1 (NRG1) treatment.
CONCLUSIONS
Our current data demonstrate the functional importance of Cdon in motor neuron function and nerve repair. Cdon ablation causes alterations in neurotrophin signalling that leads to motor neuron degeneration.
PubMed: 37559423
DOI: 10.1002/jcsm.13308 -
Cell Reports Nov 2023Motor neuron (MN) development and nerve regeneration requires orchestrated action of a vast number of molecules. Here, we identify SorCS2 as a progranulin (PGRN)...
Motor neuron (MN) development and nerve regeneration requires orchestrated action of a vast number of molecules. Here, we identify SorCS2 as a progranulin (PGRN) receptor that is required for MN diversification and axon outgrowth in zebrafish and mice. In zebrafish, SorCS2 knockdown also affects neuromuscular junction morphology and fish motility. In mice, SorCS2 and PGRN are co-expressed by newborn MNs from embryonic day 9.5 until adulthood. Using cell-fate tracing and nerve segmentation, we find that SorCS2 deficiency perturbs cell-fate decisions of brachial MNs accompanied by innervation deficits of posterior nerves. Additionally, adult SorCS2 knockout mice display slower motor nerve regeneration. Interestingly, primitive macrophages express high levels of PGRN, and their interaction with SorCS2-positive motor axon is required during axon pathfinding. We further show that SorCS2 binds PGRN to control its secretion, signaling, and conversion into granulins. We propose that PGRN-SorCS2 signaling controls MN development and regeneration in vertebrates.
Topics: Mice; Animals; Progranulins; Zebrafish; Intercellular Signaling Peptides and Proteins; Motor Neurons; Granulins; Mice, Knockout; Nerve Tissue Proteins; Receptors, Cell Surface
PubMed: 37897724
DOI: 10.1016/j.celrep.2023.113333 -
Molecular Neurodegeneration Oct 2023Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, resulting in muscle... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, resulting in muscle weakness, atrophy, paralysis, and eventually death. Motor cortical hyperexcitability is a common phenomenon observed at the presymptomatic stage of ALS. Both cell-autonomous (the intrinsic properties of motor neurons) and non-cell-autonomous mechanisms (cells other than motor neurons) are believed to contribute to cortical hyperexcitability. Decoding the pathological relevance of these dynamic changes in motor neurons and glial cells has remained a major challenge. This review summarizes the evidence of cortical hyperexcitability from both clinical and preclinical research, as well as the underlying mechanisms. We discuss the potential role of glial cells, particularly microglia, in regulating abnormal neuronal activity during the disease progression. Identifying early changes such as neuronal hyperexcitability in the motor system may provide new insights for earlier diagnosis of ALS and reveal novel targets to halt the disease progression.
Topics: Humans; Amyotrophic Lateral Sclerosis; Motor Neurons; Neuroglia; Microglia; Disease Progression
PubMed: 37858176
DOI: 10.1186/s13024-023-00665-w