Tau filaments from amyotrophic lateral sclerosis/parkinsonism-dementia complex adopt the CTE fold.

The amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of the island of Guam and the Kii peninsula of Japan is a fatal neurodegenerative disease of unknown cause that is characterized by the presence of abundant filamentous tau inclusions in brains and spinal cords. Here, we used electron cryo-microscopy to determine the structures of tau filaments from the cerebral cortex of three cases of ALS/PDC from Guam and eight cases from Kii, as well as from the spinal cord of two of the Guam cases. Tau filaments had the chronic traumatic encephalopathy (CTE) fold, with variable amounts of Type I and Type II filaments. Paired helical tau filaments were also found in three Kii cases and tau filaments with the corticobasal degeneration fold in one Kii case. We identified a new Type III CTE tau filament, where protofilaments pack against each other in an antiparallel fashion. ALS/PDC is the third known tauopathy with CTE-type filaments and abundant tau inclusions in cortical layers II/III, the others being CTE and subacute sclerosing panencephalitis. Because these tauopathies are believed to have environmental causes, our findings support the hypothesis that ALS/PDC is caused by exogenous factors.

The neostriatum in polyglutamine diseases: preferential decreases in large neurons in dentatorubral-pallidoluysian atrophy and Machado-Joseph disease and in small neurons in Huntington disease.

The presence of polyglutamine-immunoreactive deposits in neurons of the neostriatum has been reported in dentatorubral-pallidoluysian atrophy (DRPLA), Machado-Joseph disease (MJD), and Huntington disease (HD). However, among these diseases, precise quantitative investigations on neurons have been performed only for HD. Changes in the number of neurons and the immunohistological features of polyglutamine deposits in the caudate head and putamen were examined in six patients with DRPLA, three with MJD, and four with HD. In the neostriatum in DRPLA, the numbers of large and small neurons were reduced to 33-38% and 48-68% relative to controls, respectively, whereas the corresponding figures in MJD were 19-26% and 65-76%, respectively, and those in HD were 34-35% and 12-16%, respectively. In DRPLA, 2-55% of neurons remaining in the neostriatum showed diffuse nuclear accumulation of polyglutamine, in contrast to 3-20% in MJD and a few percent in HD. These findings indicate that, in the neostriatum, a decrease in the number of small neurons is predominant in HD, whereas a decrease in the number of large neurons is predominant in DRPLA and MJD. Thus, it is suggested that disease processs differ among polyglutamine diseases.

Spread of vimentin-immunoreactive cells within the plaque-like lesion in the spinal anterior horn of a patient with post-poliomyelitis syndrome.

A Japanese man in the present study experienced acute weakness in his right leg as a two year old. The strength in his leg gradually recovered and developed, and he could play golf and climb mountains up to around the age of 50. From approximately 55 years of age, he became unable to stand up from a stooped position. Muscle weakness and atrophy spread to his right arm, and an electromyography revealed a neurogenic pattern in his lower and upper extremities. The patient was diagnosed as having post-poliomyelitis syndrome (PPS). Numbness in both the legs and pain in the buttocks occurred after 60 years of age. Computed tomography and magnetic resonance imaging at that time revealed spondylosis and protrusion of an osteophye in lower thoracic vertebrae compressing the second lumbar segment of the spinal cord. He died of malignant lymphoma and acute interstitial pneumonia at 80 years of age. Pathological examination revealed transverse myelopathy at the second lumbar segment of the spinal cord and total necrosis. The anterior horn and the intermediate zone of the third and fourth lumbar segments of the spinal cord on the right side were atrophic and diffusely gliotic. An oval-shaped plaque-like lesion was observed in the right anterior horn at the third and fourth lumbar segments of the spinal cord. Neurons and synaptophysin immunoreactivity had completely disappeared in the plaque-like lesion. A striking spread of vimentin-immunoreactive cells was found corresponding to the lesion, while glial fibrillary acidic protein-immunoreactive astrocytes existed evenly in the anterior horn and intermediate zone on both sides of the third and fourth lumber segments of the spinal cord. Virological examination using the autopsied materials was negative for poliovirus. Neither transactivation response DNA-binding protein of 43 kDa-immunoreactive inclusion nor Bunina body was seen in the spinal cord. The present paper demonstrates new findings of a noteworthy response of the vimentin-immunoreactive cells within the peculiar "plaque-like lesion" in the PPS.

Neuromyelitis optica spectrum disorder with massive basal ganglia involvement: a case report.

BACKGROUND: Occurrence of basal ganglia involvement in neuromyelitis optica spectrum disorders (NMOSD) has rarely been reported and none documented pathologically. CASE PRESENTATION: A 73-year-old female was clinically diagnosed with a NMOSD based on the clinical and radiological features and positive serum autoantibodies to AQP4. One month before her death, she became acutely ill with disturbed consciousness and right hemiparesis, and was diagnosed and treated as having basal ganglia infarction based on the brain CT. She made a partial recovery but later died from heart failure. At autopsy, the corresponding basal ganglia process revealed a large fresh area of necrosis. Histologically, several pathological signatures of NMOSD could be recognized in the lesion, including inflammatory cell infiltrations by B and T lymphocytes, perivascular complement and fibrinogen deposition, and the appearance of numerous phagocytosed corpora amylacea within the infiltrating macrophages. CONCLUSIONS: The present case illustrates that basal ganglia may be directly involved in the pathological processes of NMOSD, although the possibility of modification of the lesions by superimposed regional ischemia could not be excluded.

Atypical lower motor neuron disease with enlargement of Nissl substance: Report of an autopsy case.

The patient was an 81-year-old woman diagnosed with atypical motor neuron disease who died after a long clinical course (7.5 years without mechanical assistance of ventilation) characterized by lower motor neuron signs and symptoms. Upper motor neuron signs and cognitive impairment were not apparent. Autopsy demonstrated severe neuronal loss in the anterior horn of the spinal cord, and some of the remaining neurons showed enlargement of Nissl substance and apparent thickening of the nuclear envelopes. No Bunina bodies, skein-like inclusions, or structures immunoreactive for phosphorylated transactivation response DNA-binding protein 43 were found. Immunoreactivity for superoxide dismutase-1 was focally seen in the enlarged Nissl substance. Ultrastructural examination demonstrated an increase of rough-surfaced endoplasmic reticulum (rough ER) and free ribosomes, disaggregation of polyribosomes, and dispersion of free ribosomes. Cisterns of rough ER were slightly dilated, and some of them were closely attached to the nuclear envelopes. Enlargement of Nissl substance may be related to "ER stress", and the abnormal findings of rough ER and free ribosomes may represent a degenerative process. However, another possibility, that they represent a compensatory hyperplastic change, cannot be excluded. The close attachment of cisterns of rough ER to the nuclear envelopes may be a mechanism to support or compensate for the abnormally-fragile nuclear envelopes.
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First pathological report of a de novo CD5-positive diffuse large B-cell lymphoma patient presenting with Guillain-Barré syndrome-like neuropathy due to neurolymphomatosis.

Peripheral neuropathy occurs in approximately 5% of the patients with lymphoma. Two major causes of peripheral neuropathy associated with lymphoma are neurolymphomatosis and paraneoplastic neuropathy such as demyelinating neuropathy. The differential diagnosis between neurolymphomatosis and demyelinating neuropathy is difficult, because electrophysiological findings suggestive of demyelination are frequently observed even in patients with neurolymphomatosis. Here, we report a patient with de novo CD5-positive diffuse large B-cell lymphoma (DLBCL) who presented with Guillain-Barré syndrome (GBS)-like neuropathy. Demyelination due to paraneoplastic neuropathy was clinically suspected. However, autopsy demonstrated that the cause of the neuropathy was neurolymphomatosis. Clinical courses of neurolymphomatosis vary and neurolymphomatosis cases presenting with GBS-like neuropathy are reported. In addition, DLBCL is the most frequent histological type of malignant lymphoma that develops neurolymphomatosis. Furthermore, "CD5-positive" DLBCL may tend to develop neurolymphomatosis. If a patient with "CD5-positive" DLBCL develops peripheral neuropathy, neurolymphomatosis should be considered and imaging studies performed and, if possible, nerve tissue biopsy, regardless of clinical symptoms of the neuropathy. To our knowledge, this is the first report of a patient with de novo CD5-positive DLBCL with neurolymphomatosis who presented with GBS-like neuropathy.

Novel intracytoplasmic inclusions immunoreactive for phosphorylated-TDP43 and cystatin C in anterior horn cells in a case of sporadic amyotrophic lateral sclerosis.

Novel intracytoplasmic inclusions immunoreactive for phosphorylated transactivation response DNA-binding protein 43 (p-TDP43), cystatin C, and transferrin were found in anterior horn cells in a case of sporadic amyotrophic lateral sclerosis (ALS). The patient was a 59-year-old woman, who died of ALS after a clinical course of 8 years. She had been receiving mechanical support for respiration for 6 years and in a "totally locked-in" state for 4 years prior to death. The spinal cord showed severe degeneration involving the anterior and lateral funiculi, whereas the posterior funiculus was preserved. Neurons in the anterior horn and Clarke's column were markedly lost, and many Bunina bodies and a few skein-like inclusions were found. Some remaining anterior horn cells had round and densely eosinophilic or amphophilic intracytoplasmic inclusions. They were immunoreactive for ubiquitin, p-TDP43, cystatin C and transferrin. On confocal laser microscopy, cystatin C was found to consistently surround p-TDP43 within the inclusions. The inclusions ultrastructurally consisted of granule-associated fibrils and, in the central portion, dense aggregates of fibrils were associated with masses of electron-dense, coarsely granular or amorphous material. Although their pathogenesis remains unknown, these unique inclusions may have been formed under a specific condition whereby p-TDP43 and cystatin C interacted with each other.

Zinc transporters ZnT3 and ZnT6 are downregulated in the spinal cords of patients with sporadic amyotrophic lateral sclerosis.

The loss of homeostasis of essential metals is associated with various diseases, including neurodegenerative diseases. Previous studies have shown that the levels of zinc (Zn) are significantly higher in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS). Zn transporters and metallothioneins tightly control intracellular and extracellular Zn levels. This study investigated the protein levels of ZnT, a Zn transporter family, in ALS patients and model mice. The mRNA expression of ZnT1, -3, -4, -5, -6, -7, and -10 was assessed in the spinal cords of human control subjects. ZnT3 and ZnT6 protein levels were significantly diminished in the spinal cords of sporadic ALS patients compared with controls. Furthermore, immunohistochemical staining demonstrated decreased ZnT3 and ZnT6 immunoreactivity in the ventral horn of the spinal cords in ALS patients. Moreover, immunohistochemical analysis revealed that all ZnTs expressed in the spinal cords were localized in a distinct subset of motor neurons. In addition, ZnT3 and ZnT6 protein levels were not altered in SOD1 (G93A) mutant transgenic mice before or after the onset of ALS symptoms compared with controls. These results suggest that ZnT3 and ZnT6 protein levels are decreased in the spinal cords of sporadic ALS patients; however, this did not occur merely via loss of motor neurons.

Marked preservation of the visual and olfactory pathways in ALS patients in a totally locked-in state.

MATERIALS AND METHODS: The present paper examines the brains and spinal cords in 7 patients with amyotrophic lateral sclerosis (ALS) receiving artificial respirator support in a totally locked-in state (TLS) neuropathologically in order to clarify whether any anatomical structures in the central nervous system are preserved. RESULTS AND CONCLUSION: We found that the visual and olfactory pathways, hypothalamus, nucleus basalis of Meynert, and commissura anterior were remarkably well preserved, whereas the somatosensory, auditory, and gustatory pathways in the brain stem and/or spinal cord showed severe deterioration.

Hippocampal sclerosis in the parkinsonism-dementia complex of Guam: quantitative examination of neurons, neurofibrillary tangles, and TDP-43 immunoreactivity in CA1.

The cornu ammonis 1 (CA1) area in the hippocampus of the parkinsonism-dementia complex (PDC) of Guam was examined quantitatively with special references to the number of neurons, intraneuronal (i) and extracellular (e) neurofibirillary tangles (NFTs), and TDP-43 (43-kDa trans-activation-responsive region DNA-binding protein)-immunopositive structures, in 24 Chamorro patients with PDC of Guam and seven control Chamorro Guamanians (both groups having no ischemic or anoxic complications). The results were that: (i) in the patients with mildly involved PDC, total numbers of neurons, iNFTs and eNFTs were almost the same as those of neurons of controls; (ii) in patients severely involved, total numbers of neurons, iNFTs and eNFTs decreased markedly; (iii) the decrease of the number of pyramidal neurons in CA1 with positive nuclear TDP-43 was intimately correlated with the decrease in total neuron numbers; (iv) whereas the numbers of neurons and TDP-43-immunopositive intracytoplasmic aggregation in the CA1 area were inversely correlated; and (v) depression of nuclear TDP-43 immuonostainability was not affected by the presence or absence of NFTs. In conclusion, hippocampal sclerosis exists in PDC; there is a possibility of elimination of eNFTs which appeared in the CA1 in patients with PDC and loss of the neurons correlates with disappearance of nuclear TDP-43, but not with appearance of intraneurocytoplasmic TDP-43 aggregation or iNFTs.

Mannitol infusion immediately after reperfusion suppresses the development of focal cortical infarction after temporary cerebral ischemia in gerbils.

Previously we found that, after temporary cerebral ischemia, microvasculogenic secondary focal cerebral cortical ischemia occurred, caused by microvascular obstruction due to compression by swollen astrocytic end-feet, resulting in focal infarction. Herein, we examined whether mannitol infusion immediately after restoration of blood flow could protect the cerebral cortex against the development of such an infarction. If so, the infusion of mannitol might improve the results of vascular reperfusion therapy. We selected stroke-positive animals during the first 10 min after left carotid occlusion performed twice with a 5-h interval, and allocated them into four groups: sham-operated control, no-treatment, mannitol-infusion, and saline-infusion groups. Light- and electron-microscopic studies were performed on cerebral cortices of coronal sections prepared at the chiasmatic level, where the focal infarction develops abruptly in the area where disseminated selective neuronal necrosis is maturing. Measurements were performed to determine the following: (A) infarct size in HE-stained specimens from all groups at 72 and 120 h after return of blood flow; (B) number of carbon-black-suspension-perfused microvessels in the control and at 0.5, 3, 5, 8, 12 and 24 h in the no-treatment and mannitol-infusion groups; (C) area of astrocytic end-feet; and (D) number of mitochondria in the astrocytic end-feet in electron microscopic pictures taken at 5 h. The average decimal fraction area ratio of infarct size in the mannitol group was significantly reduced at 72 and 120 h, associated with an increased decimal fraction number ratio of carbon-black-suspension-perfused microvessels at 3, 5 and 8 h, and a marked reduction in the size of the end-feet at 5 h. Mannitol infusion performed immediately after restitution of blood flow following temporary cerebral ischemia remarkably reduced the size of the cerebral cortical focal infarction by decreasing the swelling of the end-feet, thus preventing the microvascular compression and stasis and thereby microvasculogenic secondary focal cerebral ischemia.

Distinctive features of degenerating Purkinje cells in spinocerebellar ataxia type 31.

Spinocerebellar ataxia type 31 (SCA31) is an autosomal dominant form of pure cerebellar ataxia that is caused by a disease-specific insertion containing penta-nucleotide repeats (TGGAA)n . Neuropathologically, cerebellar Purkinje cells are preferentially affected and reduced in number in SCA31, and they are often surrounded by halo-like amorphous materials. In the present study, we performed neuropathological analyses on two SCA31 brains, and discussed the serial morphological changes of Purkinje cells in SCA31.We found that bent, elongated, often folded nuclei were observed frequently in degenerating Purkinje cells with the halo-like structure. Conversely, Purkinje cells without this structure developed marked atrophy with severely slender and condensed nuclei. On the basis of these pathological findings, we propose two different processes for Purkinje cell degeneration in SCA31, namely, shrinkage of Purkinje cells with or without the halo-like amorphous materials. The former, but not the latter, was considered to be specific to SCA31. Correspondingly, fragmentation of the Golgi apparatus was observed more frequently in Purkinje cells with the halo-like structure than in those without this structure. We consider that the profound nuclear deformity and fragmentation of the Golgi apparatus are closely linked with the formation of the halo-like structure in SCA31.

"Gliomatosis encephali" as a novel category of brain tumors by the first autopsy case report of gliomatosis cerebelli.

Gliomatosis cerebri is a rare diffuse glioma that is neither mass-forming nor necrotic, and does not disrupt existing structures. Gliomatosis occurring in the cerebellum is known as gliomatosis cerebelli, and only three such cases examined by biopsy have been reported. Here we describe the first autopsy findings of a patient who was diagnosed as having gliomatosis in the cerebellum. Neuropathological examination identified the tumor cells as being positive for glial fibrillary acidic protein, vimentin and nestin, with atypical nuclei that were cashew-nut- or dishcloth-gourd-shaped. These tumor cells were dense in the right cerebellum, but also spread broadly throughout the brain including the left cerebrum and optic nerve. Mitotic figures were frequently seen in the cerebellum, brain stem and cerebrum. Scherer's secondary structures were evident not only in the cerebellum but also the cerebrum. No necrosis, microvascular proliferation or destruction of anatomical structures was detected in the whole brain. Differences in the origin of the tumors of the gliomatoses cerbri and cerebelli suggests these tumors are different types of brain tumors. Thus the findings support that the gliomatosis cerebelli is a novel type of brain tumor classification. Furthermore, by the similarities of the histological features among the tumors, it appears appropriate to establish a novel category of "gliomatosis encephali" which includes both gliomatosis cerebri and gliomatosis cerebelli.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): Estimation of pathological lesion stage from brain images.

BACKGROUND: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a disease responsible for cognitive impairment in adult humans. It is caused by mutations in the colony stimulating factor 1 receptor gene (CSF1R) or alanyl-transfer (t) RNA synthetase 2 (AARS2) gene and affects brain white matter. Settlement of stages of the pathological brain lesions (Oyanagi et al. 2017) from the findings of brain imaging will be inevitably essential for prognostication. METHODS: MRI images of eight patients with ALSP were analyzed semiquantitatively. White matter degeneration was assessed on a scale of 0 to 4 (none, patchy, large patchy, confluent, and diffuse) at six anatomical points, and brain atrophy on a scale 0 to 4 (none, slight, mild, moderate, and severe) in four anatomical areas. The scores of the two assessments were then summed to give total MRI scores of 0-40 points. Based on the scores, the MRI features were classified as Grades (0-4). Regression analysis was applied to mutual association between mRS, white matter degeneration score, brain atrophy score, the total MRI score and disease duration. RESULTS: White matter degeneration score, brain atrophy score, and the total MRI score were significantly correlated with the disease duration. MRI Grades (2-4) based on the total MRI scores and the features of the images were well correlated with the pathological lesion stages (II - IV); i.e., 'large patchy' white matter degeneration in the frontal and parietal lobes (MRI Grade 2) corresponded to pathological Stage II, 'confluent' degeneration (Grade 3) to Stage III, and 'diffuse' degeneration (Grade 4) to Stage IV. CONCLUSION: MRI Grades (2-4) resulted from the total MRI scores were well correlated with the pathological lesion Stages (II - IV).

Astrocytic involvement in the maturation phenomenon after temporary cerebral ischemia.

Astrocytes support neuronal functions by regulating the extracellular ion homeostasis and levels of neurotransmitters, and by providing fuel such as lactate to the neurons via their processes (APs). After two 10-min unilateral carotid occlusions with a 5-h interval in gerbils, we investigated maturing disseminated selective neuronal necrosis (DSNN) on the coronal surface sectioned at the infundibular level. We chronologically counted the normal appearing, degenerated, and dead neurons and astrocytes in the cerebral cortex; observed the ultrastructure of APs, and counted the number of their cut-ends and mitochondria in the neuropil; determined the percentage volume of APs according to Weibel's point-counting method; compared the number of cut-ends and mitochondria and percentage volume of APs around the astrocytes and around the normal-appearing, degenerated, and dead -neurons. Heterogeneous degeneration of APs was concluded to be closely associated with the maturation of DSNN.Using the same model, at the coronally sectioned surface on the chiasmatic level, we investigated the mechanism of development of focal infarction in the maturing DSNN. Same as in the above study, we chronologically counted various neurons and astrocytes; observed and measured the area of the ultrastructure of astrocytic end-feet; counted the number of carbon-black-suspension-perfused microvessels. We concluded that after temporary cerebral ischemia, secondary focal ischemia was induced by microvascular obstruction compressed by swollen astrocytic end-feet, resulting in delayed focal infarction.

Tau Filaments from Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC) adopt the CTE Fold.

The amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of the island of Guam and the Kii peninsula of Japan is a fatal neurodegenerative disease of unknown cause that is characterised by the presence of abundant filamentous tau inclusions in brains and spinal cords. Here we used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments from the cerebral cortex of three cases of ALS/PDC from Guam and eight cases from Kii, as well as from the spinal cord of two of the Guam cases. Tau filaments had the chronic traumatic encephalopathy (CTE) fold, with variable amounts of Type I and Type II filaments. Paired helical tau filaments were also found in two Kii cases. We also identified a novel Type III CTE tau filament, where protofilaments pack against each other in an anti-parallel fashion. ALS/PDC is the third known tauopathy with CTE-type filaments and abundant tau inclusions in cortical layers II/III, the others being CTE and subacute sclerosing panencephalitis. Because these tauopathies are believed to have environmental causes, our findings support the hypothesis that ALS/PDC is caused by exogenous factors.

[An autopsy case report of a patient with frontotemporal dementia with motor neuron disease in totally locked-in state showing hyperosmolar hyperosmotic state].

A 57-year-old man with no family history of amyotrophic lateral sclerosis (ALS) or diabetes was diagnosed with ALS, and placed in long-term care where an artificial respirator with tracheotomy was used. He was fed through a gastric fistula tube. He gradually lost the ability to communicate, and computed tomography revealed advanced atrophy of the frontotemporal lobe. He was abruptly suffered from polyuria 11 years after the onset of ALS, and was diagnosed with hyperosmolar hyperglycemic state (HHS). It recurred six years later with severe ascites and worsening of pleural effusion. He passed away 18 years after the onset of ALS. Pathological examination revealed a reduced numbers of Betz cells in the motor cortex, anterior horn cells in the spinal cord, and hypoglossal neurons. The remaining lower motor neurons and cells in the hippocampal dentate gyrus were positive for phosphorylated TDP-43. These corresponded to Type B on harmonized classification system for frontotemporal lobar degeneration (FTLD)-TDP pathology (Mackenzie, et al. 2011). Furthermore, the lateral, anterior, and anterolateral funiculi of the spinal cord, globus pallidus, thalamus, and brainstem tegmentum showed atrophy. The findings were compatible with ALS pathology in totally locked-in state (TLS). Hyalinized islets of Langerhans were observed scattered throughout the pancreas. The patient's muscles were nearly completely replaced by white, firm fat tissue. We considered that the patient's diabetic conditions contributed to the accumulation of excess fat in internal and external fat tissue as a result of the long-term dependence on enteral nutrition. Moreover, a disturbance in glucose metabolism in skeletal muscles that resulted from severe atrophy could have been another cause.

Identification of novel susceptibility loci for Guam neurodegenerative disease: challenges of genome scans in genetic isolates.

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a fatal neurodegenerative disease found in the Chamorro people of Guam and other Pacific Island populations. The etiology is unknown, although both genetic and environmental factors appear important. To identify loci for ALS/PDC, we conducted both genome-wide linkage and association analyses, using approximately 400 microsatellite markers, in the largest sample assembled to date, comprising a nearly complete sample of all living and previously sampled deceased cases. A single, large, complex pedigree was ascertained from a village on Guam, with smaller families and a case-control sample ascertained from the rest of Guam by population-based neurological screening and archival review. We found significant evidence for two regions with novel ALS/PDC loci on chromosome 12 and supportive evidence for the involvement of the MAPT region on chromosome 17. D12S1617 on 12p gave the strongest evidence of linkage (maximum LOD score, Z(max) = 4.03) in our initial scan, with additional support in the complete case-control sample in the form of evidence of allelic association at this marker and another nearby marker. D12S79 on 12q also provided significant evidence of linkage (Z(max) = 3.14) with support from flanking markers. Our results suggest that ALS/PDC may be influenced by as many as three loci, while illustrating challenges that are intrinsic in genetic analyses of isolated populations, as well as analytical strategies that are useful in this context. Elucidation of the genetic basis of ALS/PDC should improve our understanding of related neurodegenerative disorders including Alzheimer disease, Parkinson disease, frontotemporal dementia and ALS.

Transcriptional repression induces a slowly progressive atypical neuronal death associated with changes of YAP isoforms and p73.

Transcriptional disturbance is implicated in the pathology of polyglutamine diseases, including Huntington's disease (HD). However, it is unknown whether transcriptional repression leads to neuronal death or what forms that death might take. We found transcriptional repression-induced atypical death (TRIAD) of neurons to be distinct from apoptosis, necrosis, or autophagy. The progression of TRIAD was extremely slow in comparison with other types of cell death. Gene expression profiling revealed the reduction of full-length yes-associated protein (YAP), a p73 cofactor to promote apoptosis, as specific to TRIAD. Furthermore, novel neuron-specific YAP isoforms (YAPDeltaCs) were sustained during TRIAD to suppress neuronal death in a dominant-negative fashion. YAPDeltaCs and activated p73 were colocalized in the striatal neurons of HD patients and mutant huntingtin (htt) transgenic mice. YAPDeltaCs also markedly attenuated Htt-induced neuronal death in primary neuron and Drosophila melanogaster models. Collectively, transcriptional repression induces a novel prototype of neuronal death associated with the changes of YAP isoforms and p73, which might be relevant to the HD pathology.