Drosophila to Explore Nucleolar Stress.

Nucleolar stress occurs when ribosome production or function declines. Nucleolar stress in stem cells or progenitor cells often leads to disease states called ribosomopathies. Drosophila offers a robust system to explore how nucleolar stress causes cell cycle arrest, apoptosis, or autophagy depending on the cell type. We provide an overview of nucleolar stress in Drosophila by depleting nucleolar phosphoprotein of 140 kDa (Nopp140), a ribosome biogenesis factor (RBF) in nucleoli and Cajal bodies (CBs). The depletion of Nopp140 in eye imaginal disc cells generates eye deformities reminiscent of craniofacial deformities associated with the Treacher Collins syndrome (TCS), a human ribosomopathy. We show the activation of c-Jun N-terminal Kinase (JNK) in Drosophila larvae homozygous for a Nopp140 gene deletion. JNK is known to induce the expression of the pro-apoptotic Hid protein and autophagy factors Atg1, Atg18.1, and Atg8a; thus, JNK is a central regulator in Drosophila nucleolar stress. Ribosome abundance declines upon Nopp140 loss, but unusual cytoplasmic granules accumulate that resemble Processing (P) bodies based on marker proteins, Decapping Protein 1 (DCP1) and Maternal expression at 31B (Me31B). Wild type brain neuroblasts (NBs) express copious amounts of endogenous coilin, but coilin levels decline upon nucleolar stress in most NB types relative to the Mushroom body (MB) NBs. MB NBs exhibit resilience against nucleolar stress as they maintain normal coilin, Deadpan, and EdU labeling levels.

MAPT subhaplotypes in corticobasal degeneration: assessing associations with disease risk, severity of tau pathology, and clinical features.

The microtubule-associated protein tau (MAPT) H1 haplotype is the strongest genetic risk factor for corticobasal degeneration (CBD). However, the specific H1 subhaplotype association is not well defined, and it is not clear whether any MAPT haplotypes influence severity of tau pathology or clinical presentation in CBD. Therefore, in the current study we examined 230 neuropathologically confirmed CBD cases and 1312 controls in order to assess associations of MAPT haplotypes with risk of CBD, severity of tau pathology (measured as semi-quantitative scores for coiled bodies, neurofibrillary tangles, astrocytic plaques, and neuropil threads), age of CBD onset, and disease duration. After correcting for multiple testing (P < 0.0026 considered as significant), we confirmed the strong association between the MAPT H2 haplotype and decreased risk of CBD (Odds ratio = 0.26, P = 2 × 10-12), and also observed a novel association between the H1d subhaplotype and an increased CBD risk (Odds ratio = 1.76, P = 0.002). Additionally, although not statistically significant after correcting for multiple testing, the H1c haplotype was associated with a higher risk of CBD (Odds ratio = 1.49, P = 0.009). No MAPT haplotypes were significantly associated with any tau pathology measures, age of CBD onset, or disease duration. Though replication will be important and there is potential that population stratification could have influenced our findings, these results suggest that several MAPT H1 subhaplotypes are primarily responsible for the strong association between MAPT H1 and risk of CBD, but that H1 subhaplotypes are unlikely to play a major role in driving tau pathology or clinical features. Our findings also indicate that similarities in MAPT haplotype risk-factor profile exist between CBD and the related tauopathy progressive supranuclear palsy, with H2, H1d, and H1c displaying associations with both diseases.

Nusinersen ameliorates motor function and prevents motoneuron Cajal body disassembly and abnormal poly(A) RNA distribution in a SMA mouse model.

Spinal muscular atrophy (SMA) is a devastating autosomal recessive neuromuscular disease characterized by degeneration of spinal cord alpha motor neurons (αMNs). SMA is caused by the homozygous deletion or mutation of the survival motor neuron 1 (SMN1) gene, resulting in reduced expression of SMN protein, which leads to αMN degeneration and muscle atrophy. The majority of transcripts of a second gene (SMN2) generate an alternative spliced isoform that lacks exon 7 and produces a truncated nonfunctional form of SMN. A major function of SMN is the biogenesis of spliceosomal snRNPs, which are essential components of the pre-mRNA splicing machinery, the spliceosome. In recent years, new potential therapies have been developed to increase SMN levels, including treatment with antisense oligonucleotides (ASOs). The ASO-nusinersen (Spinraza) promotes the inclusion of exon 7 in SMN2 transcripts and notably enhances the production of full-length SMN in mouse models of SMA. In this work, we used the intracerebroventricular injection of nusinersen in the SMN∆7 mouse model of SMA to evaluate the effects of this ASO on the behavior of Cajal bodies (CBs), nuclear structures involved in spliceosomal snRNP biogenesis, and the cellular distribution of polyadenylated mRNAs in αMNs. The administration of nusinersen at postnatal day (P) 1 normalized SMN expression in the spinal cord but not in skeletal muscle, rescued the growth curve and improved motor behavior at P12 (late symptomatic stage). Importantly, this ASO recovered the number of canonical CBs in MNs, significantly reduced the abnormal accumulation of polyadenylated RNAs in nuclear granules, and normalized the expression of the pre-mRNAs encoding chondrolectin and choline acetyltransferase, two key factors for αMN homeostasis. We propose that the splicing modulatory function of nusinersen in SMA αMN is mediated by the rescue of CB biogenesis, resulting in enhanced polyadenylated pre-mRNA transcription and splicing and nuclear export of mature mRNAs for translation. Our results support that the selective restoration of SMN expression in the spinal cord has a beneficial impact not only on αMNs but also on skeletal myofibers. However, the rescue of SMN expression in muscle appears to be necessary for the complete recovery of motor function.

Nuclear signs of pre-neurodegeneration.

Nuclear architecture is highly concerted including the organization of chromosome territories and distinct nuclear bodies, such as nucleoli, Cajal bodies, nuclear speckles of splicing factors, and promyelocytic leukemia nuclear bodies, among others. The organization of such nuclear compartments is very dynamic and may represent a sensitive indicator of the functional status of the cell. Here, we describe methodologies that allow isolating discrete cell populations from the brain and the fine observation of nuclear signs that could be insightful predictors of an early neuronal injury in a wide range of neurodegenerative disorders. The tools here described may be of use for the early detection of pre-degenerative processes in neurodegenerative diseases and for validating novel rescue strategies.

The brainstem pathologies of Parkinson's disease and dementia with Lewy bodies.

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are among the human synucleinopathies, which show alpha-synuclein immunoreactive neuronal and/or glial aggregations and progressive neuronal loss in selected brain regions (eg, substantia nigra, ventral tegmental area, pedunculopontine nucleus). Despite several studies about brainstem pathologies in PD and DLB, there is currently no detailed information available regarding the presence of alpha-synuclein immunoreactive inclusions (i) in the cranial nerve, precerebellar, vestibular and oculomotor brainstem nuclei and (ii) in brainstem fiber tracts and oligodendroctyes. Therefore, we analyzed the inclusion pathologies in the brainstem nuclei (Lewy bodies, LB; Lewy neurites, LN; coiled bodies, CB) and fiber tracts (LN, CB) of PD and DLB patients. As reported in previous studies, LB and LN were most prevalent in the substantia nigra, ventral tegmental area, pedunculopontine and raphe nuclei, periaqueductal gray, locus coeruleus, parabrachial nuclei, reticular formation, prepositus hypoglossal, dorsal motor vagal and solitary nuclei. Additionally we were able to demonstrate LB and LN in all cranial nerve nuclei, premotor oculomotor, precerebellar and vestibular brainstem nuclei, as well as LN in all brainstem fiber tracts. CB were present in nearly all brainstem nuclei and brainstem fiber tracts containing LB and/or LN. These findings can contribute to a large variety of less well-explained PD and DLB symptoms (eg, gait and postural instability, impaired balance and postural reflexes, falls, ingestive and oculomotor dysfunctions) and point to the occurrence of disturbances of intra-axonal transport processes and transneuronal spread of the underlying pathological processes of PD and DLB along anatomical pathways.

Nucleolar disruption and cajal body disassembly are nuclear hallmarks of DNA damage-induced neurodegeneration in purkinje cells.

The Purkinje cell (PC) degeneration (pcd) phenotype results from mutation in nna1 gene and is associated with the degeneration and death of PCs during the postnatal life. Although the pcd mutation is a model of the ataxic mouse, it shares clinical and pathological characteristics of inherited human spinocerebellar ataxias. PC degeneration in pcd mice provides a useful neuronal system to study nuclear mechanisms involved in DNA damage-dependent neurodegeneration, particularly the contribution of nucleoli and Cajal bodies (CBs). Both nuclear structures are engaged in housekeeping functions for neuronal survival, the biogenesis of ribosomes and the maturation of snRNPs and snoRNPs required for pre-mRNA and pre-rRNA processing, respectively. In this study, we use ultrastructural analysis, in situ transcription assay and molecular markers for DNA damage, nucleoli and CB components to demonstrate that PC degeneration involves the progressive accumulation of nuclear DNA damage associated with disruption of nucleoli and CBs, disassembly of polyribosomes into monoribosomes, ribophagy and shut down of nucleolar and extranucleolar transcription. Microarray analysis reveals that four genes encoding repressors of nucleolar rRNA synthesis (p53, Rb, PTEN and SNF2) are upregulated in the cerebellum of pcd mice. Collectively, these data support that nucleolar and CB alterations are hallmarks of DNA damage-induced neurodegeneration.

Impaired minor tri-snRNP assembly generates differential splicing defects of U12-type introns in lymphoblasts derived from a type I SMA patient.

The survival of motor neuron (SMN) protein is essential for cytoplasmic assembly of spliceosomal snRNPs. Although the normal proportion of endogenous snRNAs is unevenly altered in spinal muscular atrophy (SMA) tissues, the biogenesis of individual snRNPs is not dramatically affected in SMN-deficient cells. The SMN protein is also required for normal Cajal body (CB) formation, but the functional consequences of CB disruption upon SMN deficiency have not yet been analyzed at the level of macromolecular snRNPs assembly. Here, we show that the SMN protein is required for tri-snRNPs formation and that the level of the minor U4atac/U6atac/U5 tri-snRNPs is dramatically decreased in lymphoblasts derived from a patient suffering from a severe form of SMA. We found also that splicing of some, but not all, minor introns is inhibited in these cells, demonstrating links between SMN deficiency and differential alterations of splicing events mediated by the minor spliceosome. Our results suggest that SMA might result from the inefficient splicing of one or only a few pre-mRNAs carrying minor introns and coding for proteins required for motor neurons function and/or organization.

TDP-43 expression in mouse models of amyotrophic lateral sclerosis and spinal muscular atrophy.

BACKGROUND: Redistribution of nuclear TAR DNA binding protein 43 (TDP-43) to the cytoplasm and ubiquitinated inclusions of spinal motor neurons and glial cells is characteristic of amyotrophic lateral sclerosis (ALS) pathology. Recent evidence suggests that TDP-43 pathology is common to sporadic ALS and familial ALS without SOD1 mutation, but not SOD1-related fALS cases. Furthermore, it remains unclear whether TDP-43 abnormalities occur in non-ALS forms of motor neuron disease. Here, we characterise TDP-43 localisation, expression levels and post-translational modifications in mouse models of ALS and spinal muscular atrophy (SMA). RESULTS: TDP-43 mislocalisation to ubiquitinated inclusions or cytoplasm was notably lacking in anterior horn cells from transgenic mutant SOD1G93A mice. In addition, abnormally phosphorylated or truncated TDP-43 species were not detected in fractionated ALS mouse spinal cord or brain. Despite partial colocalisation of TDP-43 with SMN, depletion of SMN- and coilin-positive Cajal bodies in motor neurons of affected SMA mice did not alter nuclear TDP-43 distribution, expression or biochemistry in spinal cords. CONCLUSION: These results emphasise that TDP-43 pathology characteristic of human sporadic ALS is not a core component of the neurodegenerative mechanisms caused by SOD1 mutation or SMN deficiency in mouse models of ALS and SMA, respectively.

Interstitial cells of Cajal in diabetic gastroenteropathy.

Gastroenteropathy causes considerable morbidity in patients with diabetes mellitus and represents a major healthcare burden. Current treatments are largely symptomatic and frequently ineffective. Development of new therapeutic options is hampered by poor understanding of the underlying pathomechanisms. Experimental studies and sparse human data indicate that diabetic gastroenteropathy is multifactorial and involves not only parasympathetic and sympathetic autonomic nerves, but also enteric neurons, smooth muscle cells and interstitial cells of Cajal (ICC). ICC are mesenchymal cells that occur throughout the muscular coat of the gastrointestinal tract and provide functions critical for normal gastrointestinal motility including generation and propagation of electrical slow waves and mediation of bidirectional communication between the autonomic nervous system and smooth muscle cells. Through these functions, and in concert with other cell types of the gastrointestinal muscles, ICC support basic gastrointestinal functions such as digestion, absorption and waste removal. Loss or dysfunction of ICC in various dysmotilities and their animal models has been shown to lead to gastric dysrhythmias, gastroparesis, slow intestinal transit, impaired neuroeffector mechanisms and altered visceral afferent signalling that are considered hallmarks of diabetic gastroenteropathy. These findings and an increasing body of evidence indicating disruptions of ICC networks in diabetes suggest that the loss of ICC in this disorder is probably of functional significance and could even be a major pathogenetic factor. Future research should focus on the identification of the molecular and cellular mechanisms underlying ICC loss in diabetes and the translation of the experimental findings into treatments.

Targeting of SMN to Cajal bodies is mediated by self-association.

The childhood autosomal recessive disorder spinal muscular atrophy (SMA) is caused by mutations in the survival motor neuron (SMN) gene. SMN localizes diffusely in the cytoplasm and in distinct nuclear structures called Cajal bodies. Cajal bodies are believed to be the storage and processing sites of several ribonucleoproteins. Here, using a novel panel of SMN exon deletion constructs, we report a systematic analysis of internal targeting domains in the SMN protein. We demonstrate that the peptides encoded by exons 2b, 3 and 6 perform an integral role in the cellular targeting of SMN. In addition, we identify a nine amino acid motif within the highly conserved sequences of the exon 2b encoded domain that mediates Cajal body targeting and self-association. Deletion of this domain dramatically affects SMN activity and results in a dominant-negative clone. These results identify critical domains within the SMN protein and have an impact on our understanding of the SMN protein with regards to SMA as well as cellular biology.

Interstitial cells of Cajal and their role in veterinary gastrointestinal pathologies.

This study highlights the importance of interstitial cells of Cajal (ICs) in gastrointestinal disease. Human research is already considering IC pathologies but in veterinary research IC pathologies are rarely studied. Nevertheless, recent studies of ICs show a growing interest in the pathophysiology of gastrointestinal diseases and emphasize the consideration of this cell type in the pathophysiology of veterinary gastrointestinal malfunctions.

Interstitial cells of Cajal network in primary obstructive megaureter.

OBJECTIVES: Recent reports showed an altered density of interstitial cells of Cajal (ICCs) and of peripherin immunoreactive nerve fibres in obstructed uretero-pelvic junction. Our aim was to investigate ICCs immunoexpression and ureteral innervation in primary obstructive megaureter (POM). METHODS: 8 specimens of POM were obtained during tailoring. Restricted segments of ureters were divided from the dilated ones. C-kit and peripherin immunohistochemistry were performed. RESULTS: A normal distribution of ICCs was documented in both circular and longitudinal muscular layers of dilated segments. Marked muscular hypoplasia and a sparse or absent ICCs occurred in longitudinal muscular layer of restricted ureteral segments. A normal distribution of peripherin positive fibres was present in both dilated and restricted segments. CONCLUSIONS: Our data confirmed a defective muscolarization in restricted, aperistaltic POM. The lacking of ICCs in the longitudinal muscular layer is, probably, due to the absence of c-kit positive muscular embryological precursors. No alteration of peripherin immunoreactive nerve fibres network was observed in both dilated and restricted ureteral segments.

[The enteric nervous system and interstitial cells of Cajal. Changes in chronic constipation in adults]. / Enterisches Nervensystem und interstitielle Cajal-Zellen. Veränderungen bei chronischer Obstipation im Erwachsenenalter.

Intestinal innervation disorders are part of the broad etiological spectrum of chronic constipation and need to be specifically addressed in differential diagnosis. The enteric nervous system constitutes the largest peripheral nervous system of its own ("brain in the gut"), and is involved in the mediation of intestinal motility. Morphologically different nerve cell types aggregate into intramural plexus layers and release a multitude of neurotransmitters. Malformations or lesions of the enteric nervous system may lead to a severely prolonged intestinal transit time resulting in chronic constipation resistant to conservative treatment. In contrast to the early manifestation of aganglionosis, non-aganglionic or acquired alterations to the intramural nerve plexus often remain unrecognised up to adulthood. Histopathological diagnosis is carried out by enzyme or immunohistochemical staining, either on sections or whole mount preparations, allowing an optimal visualization of the nerve plexus architecture. To diagnose hypoganglionosis, enteric ganglionitis or alterations in interstitial cells of Cajal, full-thickness biopsies are required. Interstitial cells of Cajal contribute significantly to the mediation of intestinal motility by generating "slow wave" activity. In adult patients with slow-transit constipation and megacolon, the intramuscular networks of the interstitial cells of Cajal show a significantly reduced density.

Enteric ganglioneuritis and abnormal interstitial cells of Cajal: features of inflammatory bowel disease.

BACKGROUND: An increased prevalence of irritable bowel syndrome (IBS) and disturbances in cardiac and blood pressure reflexes have been described in patients with Crohn's disease (CD) and ulcerative colitis (UC). These features could be due to abnormalities in the gastrointestinal neurotransmission. The aims of this study were to examine whether histopathologic changes in the enteric nervous system correlate with disturbances in cardiac and blood pressure reflexes and the occurrence of IBS- and dyspepsia-like symptoms in these patients. METHODS: Thirty patients with CD and UC with bowel resection were examined by deep-breathing and orthostatic tests. The resection specimens were evaluated histologically regarding visceral neuro- or myopathy. All medical records were studied for treatment and clinical course. RESULTS: Ganglioneuritis was observed in 11 of 19 patients with CD and in 5 of 11 with UC. Only patients with CD had ganglioneuritis in the small intestine. Moreover, in CD the interstitial cells of Cajal (ICCs) in the small bowel showed atrophy and vacuolar degeneration, along with a reduced number of cells (P = 0.005). In UC the colonic ICCs were hyperplastic (P = 0.05) without signs of degeneration. The indices of deep-breathing and orthostatic tests were impaired, except in CD with ganglioneuritis, who showed normal test values. There were no correlations between histopathologic alterations versus IBS and dyspepsia. CONCLUSIONS: Visceral ganglioneuritis and pathologic ICCs were observed in patients with CD and UC. However, these histopathologic abnormalities could not be related to the clinical or autonomic features of the disease.

Study of interstitial cells in the penis: human study.

INTRODUCTION: Specialized pacemaker cells, similar to the interstitial cells of Cajal (ICC) of the gut, have been detected in the urinary organs and are thought to pace their motile activity. AIM: We investigated the hypothesis that such cells could also exist in the corpora cavernosa (CC) of the human penis. METHODS: During the treatment of Peyronie's disease in 11 subjects (age 42.6 +/- 3.2 SD years), 3 x 3 mm strips were excised from each of the two CC and subjected to C-kit immunohistochemistry. Controls for the specificity of the antisera consisted of incubation of the tissue with normal rabbit serum substituted for the primary antiserum. MAIN OUTCOME MEASURES: Interstitial cells similar to ICC could exist in the CC based on C-kit immunohistochemistry. RESULTS: C-kit positive branched interstitial cells were detected in the CC. They were clearly distinguishable from the smooth muscle cells that were C-kit negative and non-branched. Although the mast cells were C-kit positive, they had a smooth body surface. CONCLUSIONS: Interstitial cells have been identified in the CC. They are similar to the ICC and may be responsible for initiating the slow waves recorded from the smooth muscle cells and for controlling their activity. We assume that a deficiency or absence of these cells may affect the erectile function of the patient. Further studies are needed to explore the role of these cells in erection.

The pathogenesis of idiopathic megacolon.

BACKGROUND: Even today, the pathogenesis of idiopathic megacolon is still a subject of controversy. Anomalies of the gastrointestinal autonomous nervous system or of the smooth muscle of the muscularis propria are being considered. METHODS: Sixty-three idiopathic megacolon resections between 1997 and June 2004 were investigated. The native specimens were coiled caudo-cranially and cryostat-cut. Connective tissue was stained with picric acid/Sirius red after Delauney fixation. Immunohistochemistry was performed for collagen types I, II, III and IV, as well as smooth muscle actin, vimentin, desmin fibronectin and CD117 for interstitial cells of Cajal. The enteric nervous system was examined by enzyme histochemistry for acetylcholine-esterase, lactate dehydrogenase, succinic dehydrogenase and nitroxide synthase. RESULTS: Histologically, idiopathic megacolon was characterized by a total atrophy of the collagenous tendinous connective tissue membrane of the myenteric plexus and the tendinous collagen fibre net of the muscularis propria. Immunohistochemically, mainly collagen type III was missing in the muscularis propria. Interestingly, the incidence of idiopathic megacolon in those of the female sex was seven times more frequent than in the male sex. The myenteric plexus was normal in the majority of patients. Interstitial cells of Cajal, collagen II and IV, as well as smooth muscle actin, desmin and fibronectin showed no consistent alteration. CONCLUSION: A normally structured tendinous fibre net of muscularis propria is an essential prerequisite for effective gut peristalsis. Atrophy of the tendinous fibre net abolishes peristalsis and allows for unlimited distension of the colon. A diagnosis of idiopathic megacolon can reliably be made on a collagen stain. The normal findings of myenteric plexus support the hypothesis that a primary metabolic defect of muscularis propria may be the underlying cause of idiopathic megacolon.

FLASH is an essential component of Cajal bodies.

Cajal bodies are small nuclear organelles with a number of nuclear functions. Here we show that FLICE-associated huge protein (FLASH), originally described as a component of the apoptosis signaling pathway, is mainly localized in Cajal bodies and is essential for their structure. Reduction in FLASH expression by short hairpin RNA results in disruption of the normal architecture of the Cajal body and relocalization of its components. Because the function of FLASH in the apoptosis receptor signaling pathway has been strongly questioned, we have now identified a clear function for this protein.

Interstitial cells of Cajal in erectile dysfunction.

The corpora cavernosa (CC) evokes electric activity. Slow waves (SWs) appear to originate from interstitial cells of Cajal (ICCs), which seem to control the activity of the smooth muscle cells (SMC). The ICCs were demonstrated to exist in the CC. We investigated the hypothesis that the ICC distribution differs with each of the various ED types. The study comprised 62 men with ED: 16 neurogenic (NGED), 15 arteriogenic (AGED), 11 venogenic (VGED) and 22 psychogenic (PGED). 15 volunteers with normal erections acted as controls. The patients underwent a complete diagnostic evaluation. A biopsy of 3 x 3 mm from the CC was subjected to C-kit immunohistochemistry examination. Specificity control of the antisera consisted of incubation of the tissue with normal rabbit serum substituted for the primary antiserum. C-kit positive stellate-appearing cells resembling those of ICC were detected in the controls. The branches were either laterally located (multipolar) or lying at each pole (bipolar). They were distinguishable from the SMC, which were C-kit negative. ICC were detected in all specimens from patients with NGED and VGED, absent in 13/15 with AGED and scanty in PGED. ICC distribution was different in the various types of ED. It is suggested that this distribution interferes with SW discharge and the control of SMC activity with a resulting ED.

Familial tauopathy mimicking corticobasal degeneration an autopsy study on three siblings.

We describe a family with tauopathy involving three autopsied siblings. All of the three siblings, as well as their grandmother, exhibited parkinsonism responsive to levodopa in one of the three, later associated with a possible reduction in spontaneity, compatible with frontal lobe dysfunction. Autopsy findings shared by the three siblings included, marked degeneration in the basal ganglia, especially in the substantia nigra and mild to moderate spongiosis in the cerebral cortices (mainly frontal) with achromatic neurons and tau/Gallyas-positive spherical aggregates resembling astrocytic plaques. Widespread deposition of tau in neurons, thread-like structures and oligodendrocytes as coiled body was robust in these lesions, whereas alpha-synuclein-positive deposits were absent. These features are compatible with sporadic corticobasal degeneration (CBD). Hippocampal neurons were characterized by its non-fibrillary tau deposits in the cytoplasm, as similarly visualized with Gallyas silver stain (Gal), while the Campbell-Switzer method (CS) failed to exhibit argyrophilia. This staining profile of neuronal cytoplasm with non-fibrillary structure (tau+/Gal+/CS-) is characteristic for tau-positive cortical neurons in CBD, distinct from typical neurofibrillary tangles of Alzheimer type, positive for both Gal and CS. Moreover, degenerative change was more evident in CA2 than in CA1, as noted in some cases of tauopathy with accumulation of 4-repeat tau such as CBD. This familial tauopathy can be classified as an extremely rare example of CBD based on the distribution of characteristic lesions and staining profiles of tau-deposits.