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Brain : a Journal of Neurology Dec 2016Neuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the...
Neuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the central and peripheral nervous system, and also in the visceral organs. NIID has been considered to be a heterogeneous disease because of the highly variable clinical manifestations, and ante-mortem diagnosis has been difficult. However, since we reported the usefulness of skin biopsy for the diagnosis of NIID, the number of NIID diagnoses has increased, in particular adult-onset NIID. In this study, we studied 57 cases of adult-onset NIID and described their clinical and pathological features. We analysed both NIID cases diagnosed by post-mortem dissection and by ante-mortem skin biopsy based on the presence of characteristic eosinophilic, hyaline and ubiquitin-positive intanuclear inclusion: 38 sporadic cases and 19 familial cases, from six families. In the sporadic NIID cases with onset age from 51 to 76, dementia was the most prominent initial symptom (94.7%) as designated 'dementia dominant group', followed by miosis, ataxia and unconsciousness. Muscle weakness and sensory disturbance were also observed. It was observed that, in familial NIID cases with onset age less than 40 years, muscle weakness was seen most frequently (100%), as designated 'limb weakness group', followed by sensory disturbance, miosis, bladder dysfunction, and dementia. In familial cases with more than 40 years of onset age, dementia was most prominent (100%). Elevated cerebrospinal fluid protein and abnormal nerve conduction were frequently observed in both sporadic and familial NIID cases. Head magnetic resonance imaging showed high intensity signal in corticomedullary junction in diffusion-weighted image in both sporadic and familial NIID cases, a strong clue to the diagnosis. All of the dementia dominant cases presented with this type of leukoencephalopathy on head magnetic resonance imaging. Both sporadic and familial NIID cases presented with a decline in Mini-Mental State Examination and Frontal Assessment Battery scores. Based on these clinicopathological features, we proposed a diagnosis flow chart of adult-onset NIID. Our study suggested that the prevalence rate of adult-onset NIID may be higher than previously thought, and that NIID may be underdiagnosed. We should take NIID into account for differential diagnosis of leukoencephalopathy and neuropathy.
Topics: Adolescent; Adult; Age of Onset; Aged; Dementia; Female; Humans; Intranuclear Inclusion Bodies; Magnetic Resonance Imaging; Male; Middle Aged; Muscle Weakness; Neurodegenerative Diseases; Pedigree; Young Adult
PubMed: 27797808
DOI: 10.1093/brain/aww249 -
Journal of Neurology, Neurosurgery, and... Dec 2022Abnormal expanded GGC repeats within the gene has been confirmed as the genetic mechanism for most Asian patients with neuronal intranuclear inclusion disease (NIID).... (Observational Study)
Observational Study
BACKGROUND
Abnormal expanded GGC repeats within the gene has been confirmed as the genetic mechanism for most Asian patients with neuronal intranuclear inclusion disease (NIID). This cross-sectional observational study aimed to characterise the clinical features of -related NIID in China.
METHODS
Patients with -related NIID underwent an evaluation of clinical symptoms, a neuropsychological assessment, electrophysiological examination, MRI and skin biopsy.
RESULTS
In the 247 patients with -related NIID, 149 cases were sporadic, while 98 had a positive family history. The most common manifestations were paroxysmal symptoms (66.8%), autonomic dysfunction (64.0%), movement disorders (50.2%), cognitive impairment (49.4%) and muscle weakness (30.8%). Based on the initial presentation and main symptomology, NIID was divided into four subgroups: dementia dominant (n=94), movement disorder dominant (n=63), paroxysmal symptom dominant (n=61) and muscle weakness dominant (n=29). Clinical (42.7%) and subclinical (49.1%) peripheral neuropathies were common in all types. Typical diffusion-weighted imaging subcortical lace signs were more frequent in patients with dementia (93.9%) and paroxysmal symptoms types (94.9%) than in those with muscle weakness (50.0%) and movement disorders types (86.4%). GGC repeat sizes were negatively correlated with age of onset (r=-0.196, p<0.05), and in the muscle weakness-dominant type (median 155.00), the number of repeats was much higher than in the other three groups (p<0.05). In NIID pedigrees, significant genetic anticipation was observed (p<0.05) without repeat instability (p=0.454) during transmission.
CONCLUSIONS
NIID is not rare; however, it is usually misdiagnosed as other diseases. Our results help to extend the known clinical spectrum of -related NIID.
Topics: Humans; Muscle Weakness; Peripheral Nervous System Diseases; Cross-Sectional Studies; Intranuclear Inclusion Bodies; Dementia; Movement Disorders
PubMed: 36150844
DOI: 10.1136/jnnp-2022-329772 -
CGG repeat expansion in causes mitochondrial dysfunction and progressive neurodegeneration in model.Proceedings of the National Academy of... Oct 2022Neuronal intranuclear inclusion disease (NIID) is a neuromuscular/neurodegenerative disease caused by the expansion of CGG repeats in the 5' untranslated region (UTR) of...
Neuronal intranuclear inclusion disease (NIID) is a neuromuscular/neurodegenerative disease caused by the expansion of CGG repeats in the 5' untranslated region (UTR) of the gene. These repeats can be translated into a polyglycine-containing protein, uN2CpolyG, which forms protein inclusions and is toxic in cell models, albeit through an unknown mechanism. Here, we established a transgenic model expressing uN2CpolyG in multiple systems, which resulted in progressive neuronal cell loss, locomotor deficiency, and shortened lifespan. Interestingly, electron microscopy revealed mitochondrial swelling both in transgenic flies and in muscle biopsies of individuals with NIID. Immunofluorescence and immunoelectron microscopy showed colocalization of uN2CpolyG with mitochondria in cell and patient samples, while biochemical analysis revealed that uN2CpolyG interacted with a mitochondrial RNA binding protein, LRPPRC (leucine-rich pentatricopeptide repeat motif-containing protein). Furthermore, RNA sequencing (RNA-seq) analysis and functional assays showed down-regulated mitochondrial oxidative phosphorylation in uN2CpolyG-expressing flies and NIID muscle biopsies. Finally, idebenone treatment restored mitochondrial function and alleviated neurodegenerative phenotypes in transgenic flies. Overall, these results indicate that transgenic flies expressing uN2CpolyG recapitulate key features of NIID and that reversing mitochondrial dysfunction might provide a potential therapeutic approach for this disorder.
Topics: 5' Untranslated Regions; Animals; Animals, Genetically Modified; Drosophila; Intranuclear Inclusion Bodies; Leucine; Mitochondria; Neurodegenerative Diseases; RNA-Binding Proteins; Trinucleotide Repeat Expansion
PubMed: 36191230
DOI: 10.1073/pnas.2208649119 -
Cells Aug 2019Promyelocytic leukemia (PML) bodies are dynamic intracellular structures that recruit and release a variety of different proteins in response to stress, virus infection,... (Review)
Review
Promyelocytic leukemia (PML) bodies are dynamic intracellular structures that recruit and release a variety of different proteins in response to stress, virus infection, DNA damage and cell cycle progression. While PML bodies primarily are regarded as nuclear compartments, they are forced to travel to the cytoplasm each time a cell divides, due to breakdown of the nuclear membrane at entry into mitosis and subsequent nuclear exclusion of nuclear material at exit from mitosis. Here we review the biochemical and biophysical transitions that occur in PML bodies during mitosis and discuss this in light of post-mitotic nuclear import, cell fate decision and acute promyelocytic leukemia therapy.
Topics: Active Transport, Cell Nucleus; Animals; Cell Nucleus; Cells, Cultured; Cytoplasm; Humans; Intranuclear Inclusion Bodies; Leukemia, Promyelocytic, Acute; Mice; Mitosis; Nuclear Envelope; Promyelocytic Leukemia Protein
PubMed: 31416160
DOI: 10.3390/cells8080893 -
Molecular Cell Aug 2020Despite the prominent role of TDP-43 in neurodegeneration, its physiological and pathological functions are not fully understood. Here, we report an unexpected role of...
Despite the prominent role of TDP-43 in neurodegeneration, its physiological and pathological functions are not fully understood. Here, we report an unexpected role of TDP-43 in the formation of dynamic, reversible, liquid droplet-like nuclear bodies (NBs) in response to stress. Formation of NBs alleviates TDP-43-mediated cytotoxicity in mammalian cells and fly neurons. Super-resolution microscopy reveals distinct functions of the two RRMs in TDP-43 NB formation. TDP-43 NBs are partially colocalized with nuclear paraspeckles, whose scaffolding lncRNA NEAT1 is dramatically upregulated in stressed neurons. Moreover, increase of NEAT1 promotes TDP-43 liquid-liquid phase separation (LLPS) in vitro. Finally, we discover that the ALS-associated mutation D169G impairs the NEAT1-mediated TDP-43 LLPS and NB assembly, causing excessive cytoplasmic translocation of TDP-43 to form stress granules, which become phosphorylated TDP-43 cytoplasmic foci upon prolonged stress. Together, our findings suggest a stress-mitigating role and mechanism of TDP-43 NBs, whose dysfunction may be involved in ALS pathogenesis.
Topics: Amyotrophic Lateral Sclerosis; Animals; Animals, Genetically Modified; Arsenites; Cerebral Cortex; Cytoplasmic Granules; DNA-Binding Proteins; Disease Models, Animal; Drosophila melanogaster; Gene Expression Regulation; HEK293 Cells; HeLa Cells; Humans; Intranuclear Inclusion Bodies; Mice; Mutation; Neurons; Primary Cell Culture; Protein Transport; RNA, Long Noncoding; Signal Transduction; Stress, Physiological
PubMed: 32649883
DOI: 10.1016/j.molcel.2020.06.019 -
Neuron Jun 2021Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by the presence of intranuclear inclusions of unknown origin. NIID is caused...
Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by the presence of intranuclear inclusions of unknown origin. NIID is caused by an expansion of GGC repeats in the 5' UTR of the NOTCH2NLC (N2C) gene. We found that these repeats are embedded in a small upstream open reading frame (uORF) (uN2C), resulting in their translation into a polyglycine-containing protein, uN2CpolyG. This protein accumulates in intranuclear inclusions in cell and mouse models and in tissue samples of individuals with NIID. Furthermore, expression of uN2CpolyG in mice leads to locomotor alterations, neuronal cell loss, and premature death of the animals. These results suggest that translation of expanded GGC repeats into a novel and pathogenic polyglycine-containing protein underlies the presence of intranuclear inclusions and neurodegeneration in NIID.
Topics: Animals; Cell Death; Cell Nucleus; Cells, Cultured; HEK293 Cells; Humans; Intranuclear Inclusion Bodies; Locomotion; Male; Mice; Mice, Inbred C57BL; Neurodegenerative Diseases; Open Reading Frames; Peptides; Trinucleotide Repeat Expansion
PubMed: 33887199
DOI: 10.1016/j.neuron.2021.03.038 -
Acta Neuropathologica Communications May 2022Recently, inspired by the similar clinical and pathological features shared with fragile X-associated tremor/ataxia syndrome (FXTAS), abnormal expansion of CGG repeats... (Review)
Review
Recently, inspired by the similar clinical and pathological features shared with fragile X-associated tremor/ataxia syndrome (FXTAS), abnormal expansion of CGG repeats in the 5' untranslated region has been found in neuronal intranuclear inclusion disease (NIID), oculopharyngeal myopathy with leukoencephalopathy (OPML), and oculopharyngodistal myopathy (OPDMs). Although the upstream open reading frame has not been elucidated in OPML and OPDMs, polyglycine (polyG) translated by expanded CGG repeats is reported to be as a primary pathogenesis in FXTAS and NIID. Collectively, these findings indicate a new disease entity, the polyG diseases. In this review, we state the common clinical manifestations, pathological features, mechanisms, and potential therapies in these diseases, and provide preliminary opinions about future research in polyG diseases.
Topics: Ataxia; Fragile X Mental Retardation Protein; Fragile X Syndrome; Humans; Intranuclear Inclusion Bodies; Muscular Dystrophies; Neurodegenerative Diseases; Peptides; Tremor
PubMed: 35642014
DOI: 10.1186/s40478-022-01383-y -
Neurology India 2023
Topics: Humans; Intranuclear Inclusion Bodies; Neurodegenerative Diseases; Neurons
PubMed: 37929491
DOI: 10.4103/0028-3886.388068 -
Science Advances Nov 2022GGC repeat expansions within have been identified as the genetic cause of neuronal intranuclear inclusion disease (NIID). To understand the molecular pathogenesis of...
GGC repeat expansions within have been identified as the genetic cause of neuronal intranuclear inclusion disease (NIID). To understand the molecular pathogenesis of NIID, here, we established both a transgenic mouse model and a human neural progenitor cells (hNPCs) model. Expression of the with expanded GGC repeats produced widespread intranuclear and perinuclear polyglycine (polyG), polyalanine (polyA), and polyarginine (polyR) inclusions, leading to behavioral deficits and severe neurodegeneration, which faithfully mimicked the clinical and pathological features associated with NIID. Furthermore, conserved alternative splicing events were identified between the NIID mouse and hNPC models, among which was the enrichment of the binding motifs of hnRNPM, an RNA binding protein known as alternative splicing regulator. Expanded NOTCH2NLC-polyG and NOTCH2NLC-polyA could interact with and sequester hnRNPM, while overexpression of hnRNPM could ameliorate the cellular toxicity. These results together suggested that dysfunction of hnRNPM could play an important role in the molecular pathogenesis of NIID.
Topics: Animals; Humans; Mice; Disease Models, Animal; Intranuclear Inclusion Bodies; Neurodegenerative Diseases; RNA-Binding Proteins
PubMed: 36417528
DOI: 10.1126/sciadv.add6391 -
Cold Spring Harbor Perspectives in... Sep 2010Orphan nuclear bodies are defined as nonchromatin nuclear compartments that have been less well studied compared with other well-characterized structures in the nucleus.... (Review)
Review
Orphan nuclear bodies are defined as nonchromatin nuclear compartments that have been less well studied compared with other well-characterized structures in the nucleus. Nuclear bodies have traditionally been thought of as uniform distinct entities depending on the protein "markers" they contain. However, it is becoming increasingly apparent that nuclear bodies enriched in different sets of transcriptional regulators share a link to the ubiquitin-proteasome and SUMO-conjugation pathways. An emerging concept is that some orphan nuclear bodies might act as sites of protein modification by SUMO and/or proteasomal degradation of ubiquitin-tagged proteins. By defining a specialized environment for protein modification and degradation, orphan nuclear bodies may increase the capacity of cells to survive under varying environmental conditions.
Topics: Animals; Humans; Intranuclear Inclusion Bodies; Proteasome Endopeptidase Complex; SUMO-1 Protein; Ubiquitin
PubMed: 20610547
DOI: 10.1101/cshperspect.a000703