Neuropathology with Clinical Correlations of Sporadic Amyotrophic Lateral Sclerosis: 102 Autopsy Cases Examined Between 1962 and 2000

Piao, Yue-Shan; Wakabayashi, Keiji; Kakita, Akiyoshi; Yamada, Mitsunori; Hayashi, Shigenari; Morita, Takashi; Ikuta, Fusahiro; Oyanagi, Kiyomitsu; Takahashi, Hitoshi

doi:10.1111/j.1750-3639.2003.tb00002.x

Cited by 181 publications

(165 citation statements)

References 66 publications

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“…The nuclear accumulation of hSOD1 and its formation of nuclear inclusions in transgenic pig brains are similar to the presence of ubiquitinated nuclear inclusions of SOD1 in the brain and spinal cord tissue of ALS patients [33,34]. Such nuclear SOD1 inclusions, however, have never been found in transgenic SOD1 mouse brains.…”

Section: Hsod1 Interacts With Pcbp1 In Pig Brainsmentioning

confidence: 58%

Species-dependent neuropathology in transgenic SOD1 pigs

Yang

Wang

Sun³

et al. 2014

Cell Res

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Mutations in the human copper/zinc superoxide dismutase 1 (hSOD1) gene cause familial amyotrophic lateral sclerosis (ALS). It remains unknown whether large animal models of ALS mimic more pathological events seen in ALS patients via novel mechanisms. Here, we report the generation of transgenic pigs expressing mutant G93A hSOD1 and showing hind limb motor defects, which are germline transmissible, and motor neuron degeneration in dose-and age-dependent manners. Importantly, in the early disease stage, mutant hSOD1 did not form cytoplasmic inclusions, but showed nuclear accumulation and ubiquitinated nuclear aggregates, as seen in some ALS patient brains, but not in transgenic ALS mouse models. Our findings revealed that SOD1 binds PCBP1, a nuclear poly(rC) binding protein, in pig brain, but not in mouse brain, suggesting that the SOD1-PCBP1 interaction accounts for nuclear SOD1 accumulation and that species-specific targets are key to ALS pathology in large mammals and in humans.

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Section: Hsod1 Interacts With Pcbp1 In Pig Brainsmentioning

confidence: 58%

Species-dependent neuropathology in transgenic SOD1 pigs

Yang

Wang

Sun³

et al. 2014

Cell Res

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“…We hypothesized that the interaction between the dynein motor and mutant SOD1 could play a role in the aggregation and formation of inclusions containing mutant SOD1. Several different types of inclusions occur in the spinal cords of both sporadic and familial ALS patients, including axonal spheroids, Bunina bodies, skein-like inclusions, and Lewy body-like hyaline inclusions (LBHI) (12)(13)(14)(15)(16)(17). Similar visible aggregates, predominantly LBHI, have also been observed in mutant SOD1 transgenic mice (18 -23).…”

mentioning

confidence: 64%

Interaction of Amyotrophic Lateral Sclerosis (ALS)-related Mutant Copper-Zinc Superoxide Dismutase with the Dynein-Dynactin Complex Contributes to Inclusion Formation

Ström

Shi

Zhang

et al. 2008

Journal of Biological Chemistry

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An important consequence of protein misfolding related to neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), is the formation of proteinaceous inclusions or aggregates within the central nervous system. We have previously shown that several familial ALS-linked copper-zinc superoxide dismutase (SOD1) mutants (A4V, G85R, and G93A) interact and co-localize with the dynein-dynactin complex in cultured cells and affected tissues of ALS mice. In this study, we report that the interaction between mutant SOD1 and the dynein motor plays a critical role in the formation of large inclusions containing mutant SOD1. Disruption of the motor by overexpression of the p50 subunit of dynactin in neuronal and non-neuronal cell cultures abolished the association between aggregation-prone SOD1 mutants and the dynein-dynactin complex. The p50 overexpression also prevented mutant SOD1 inclusion formation and improved the survival of cells expressing A4V SOD1. Furthermore, we observed that two ALS-linked SOD1 mutants, H46R and H48Q, which showed a lower propensity to interact with the dynein motor, also produced less aggregation and fewer large inclusions. Overall, these data suggest that formation of large inclusions depends upon association of the abnormal SOD1s with the dynein motor. Whether the misfolded SOD1s directly perturb axonal transport or impair other functional properties of the dynein motor, this interaction could propagate a toxic effect that ultimately causes motor neuron death in ALS. Amyotrophic lateral sclerosis (ALS)2 is a progressive and fatal neurodegenerative disease primarily affecting motor neurons in the spinal cord and brainstem. Approximately 10% of ALS cases are inherited, and of these ϳ20% are caused by mutations in the Cu,Zn-superoxide dismutase 1 (SOD1) gene (1, 2). To date, more than 100 mutations scattered throughout the SOD1 protein have been identified (3). Many SOD1 mutants retain nearly normal enzymatic activity, and SOD1 knock-out mice do not develop ALS (4, 5). Therefore, it is believed that mutant SOD1s acquire a toxic "gain-of-function" property.We recently identified dynein as a component of soluble SOD1-containing high molecular weight (HMW) complexes (6), which have been implicated in neuronal toxicity and may be precursors to SOD1 inclusions (7-9). Moreover, co-immunoprecipitation using tissue lysates from transgenic rodents expressing wild-type (WT), G93A, or G85R SOD1, showed that mutant SOD1 interacted with the dynein-dynactin complex to a much greater extent than did WT SOD1. The association was detected in the pre-symptomatic G93A mice (60 days), and the amount of mutant SOD1 interacting with the dynein complex increased over the disease progression (6).Dynein-mediated microtubule-dependent retrograde transport has been shown to be important for sequestration of misfolded proteins into large inclusions called aggresomes (10,11). We hypothesized that the interaction between the dynein motor and mutant SOD1 could play a role in the aggregation and formation of inc...

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“…Several ALS risk factors have been identified, but the etiology of the disease is largely unclear. A hallmark of the disease is the appearance of intracellular inclusions in degenerating motor neurons (6), both in the familial cases caused by mutations in SOD1 and in the more obscure sporadic cases (6 -11). The formation of such protein aggregates precedes neuronal death (12).…”

Section: Amyotrophic Lateral Sclerosis (Als)mentioning

confidence: 99%

p62 Accumulates and Enhances Aggregate Formation in Model Systems of Familial Amyotrophic Lateral Sclerosis

Gál

Ström

Kilty

et al. 2007

Journal of Biological Chemistry

160

123

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron death. A hallmark of the disease is the appearance of protein aggregates in the affected motor neurons. We have found that p62, a protein implicated in protein aggregate formation, accumulated progressively in the G93A mouse spinal cord. The accumulation of p62 was in parallel to the increase of polyubiquitinated proteins and mutant SOD1 aggregates. Immunostaining studies showed that p62, ubiquitin, and mutant SOD1 co-localized in the protein aggregates in affected cells in G93A mouse spinal cord. The p62 protein selectively interacted with familial ALS mutants, but not WT SOD1. When p62 was co-expressed with SOD1 in NSC34 cells, it greatly enhanced the formation of aggregates of the ALS-linked SOD1 mutants, but not wild-type SOD1. Cell viability was measured in the presence and absence of overexpressed p62, and the results suggest that the large aggregates facilitated by p62 were not directly toxic to cells under the conditions in this study. Deletion of the ubiquitin-association (UBA) domain of p62 significantly decreased the p62-facilitated aggregate formation, but did not completely inhibit it. Further protein interaction experiments also showed that the truncated p62 with the UBA domain deletion remained capable of interacting with mutant SOD1. The findings of this study show that p62 plays a critical role in forming protein aggregates in familial ALS, likely by linking misfolded mutant SOD1 molecules and other cellular proteins together. Amyotrophic lateral sclerosis (ALS)3 is a progressive neurodegenerative disorder leading to the selective death of motor neurons (1, 2). The majority of cases are sporadic, but about 10% of all cases are familial (fALS). In ϳ20% of familial cases, a mutant allele of the copper-zinc superoxide dismutase (SOD1) enzyme has been identified (3-5). As of today, over 100 different mutations of SOD1 causing ALS have been reported, the majority of which are point mutations and act in a dominant fashion. Several ALS risk factors have been identified, but the etiology of the disease is largely unclear. A hallmark of the disease is the appearance of intracellular inclusions in degenerating motor neurons (6), both in the familial cases caused by mutations in SOD1 and in the more obscure sporadic cases (6 -11). The formation of such protein aggregates precedes neuronal death (12). The inclusions are typically SOD1 and ubiquitin immunoreactive in the mutant SOD1-mediated fALS cases (2, 7-9, 11-13). However, it is unclear how the SOD1 mutants form aggregates and whether other proteins play any role in the aggregation process or the aggregate-induced toxicity.p62 (also called sequestosome 1) was first identified as a phosphotyrosine-independent ligand for the Lck SH2 domain (14). It was later found to be a polyubiquitin-binding protein (15)(16)(17). The expression of p62 is up-regulated by several stress conditions, e.g. oxidative stress (18,19), proteasome inhibition (19 -21), or p...

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Neuropathology with Clinical Correlations of Sporadic Amyotrophic Lateral Sclerosis: 102 Autopsy Cases Examined Between 1962 and 2000

Cited by 181 publications

References 66 publications

Species-dependent neuropathology in transgenic SOD1 pigs

Species-dependent neuropathology in transgenic SOD1 pigs

Interaction of Amyotrophic Lateral Sclerosis (ALS)-related Mutant Copper-Zinc Superoxide Dismutase with the Dynein-Dynactin Complex Contributes to Inclusion Formation

p62 Accumulates and Enhances Aggregate Formation in Model Systems of Familial Amyotrophic Lateral Sclerosis

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