A case of familial ALS due to multi-system proteinopathy 1 and Huntington disease

Oskarsson, Björn; Wheelock, Victoria; Benatar, Michael; Taylor, J. Paul; Joyce, Nanette C.; Chesak, David; Jin, Lee Way

doi:10.3109/21678421.2014.952238

Cited by 7 publications

(15 citation statements)

References 9 publications

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“…The finding of numerous TDP‐O‐NCIs in type C suggests that abnormal TDP‐43 in type C pathology is prone to oligomerization. In the single case of type D, a rare genetic subtype associated with VCP mutations, we did not identify TDP‐O‐NCIs or DNs (see Fig D).…”

Section: Resultsmentioning

confidence: 57%

Detection of TDP‐43 oligomers in frontotemporal lobar degeneration–TDP

Kao

Chen

Liu

et al. 2015

Annals of Neurology

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Objective The proteinaceous inclusions in TDP-43 proteinopathies such as frontotemporal lobar degeneration (FTLD)-TDP are made of high–molecular-weight aggregates of TDP-43. These aggregates have not been classified as amyloids, as prior amyloid staining results were not conclusive. Here we used a specific TDP-43 amyloid oligomer antibody called TDP-O to determine the presence and abundance of TDP-43 oligomers among different subtypes of FTLD-TDP as well as in hippocampal sclerosis (HS), which represents a non-FTLD pathology with TDP-43 inclusions. Methods Postmortem tissue from the hippocampus and anterior orbital gyrus from 54 prospectively assessed and diagnosed subjects was used for immunostaining with TDP-O. Electron microscopy was used to assess the subcellular locations of TDP-O–decorated structures. Results TDP-43 inclusions staining with TDP-O were present in FTLD-TDP and were most conspicuous for FTLD-TDP type C, the subtype seen in most patients with semantic variant primary progressive aphasia. TDP-O immunoreactivity was absent in the hippocampus of HS patients despite abundant TDP-43 inclusions. Ultrastructurally, TDP-43 oligomers resided in granular or tubular structures, frequently in close proximity to, but not within, neuronal lysosomes. Interpretation TDP-43 forms amyloid oligomers in the human brain, which may cause neurotoxicity in a manner similar to other amyloid oligomers. Oligomer formation may contribute to the conformational heterogeneity of TDP-43 aggregates and mark the different properties of TDP-43 inclusions between FTLD-TDP and HS.

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Section: Resultsmentioning

confidence: 57%

Detection of TDP‐43 oligomers in frontotemporal lobar degeneration–TDP

Kao

Chen

Liu

et al. 2015

Annals of Neurology

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“…This finding suggests that C9orf72 repeat expansion is unlikely to function as an HD disease modifier. Although the literature describes genetically confirmed cases of HD with concomitant clinical or pathologically confirmed ALS [46][47][48][49][50][51][52][53][54] and a rare case of C9orf72-associated ALS with a paternal history of HD [57], simultaneous HTT and C9orf72 repeat expansion have not been reported. Only rarely has full-penetrance repeat expansion of HTT been identified in conjunction with another disease-causing repeat expansion (ATXN8) [78].…”

Section: Discussionmentioning

confidence: 99%

“…This finding markedly increased the proportion of alternative genetic diagnoses for HD phenocopies, which was previously estimated to be achieved for only about 2-3% of cases [44,45]. Interestingly, some reports describe rare cases of genetically confirmed HD with associated clinical ALS [46][47][48][49][50][51][52][53][54] but not FTD [55], with pathologic confirmation in a few [46,47,54]. Among these HD cases with concomitant ALS, a single case had an additional pathogenic alteration in the ALS-associated VCP gene [54]; C9orf72 repeat expansion was negative for another case [47].…”

Section: Introductionmentioning

confidence: 96%

“…Interestingly, some reports describe rare cases of genetically confirmed HD with associated clinical ALS [46][47][48][49][50][51][52][53][54] but not FTD [55], with pathologic confirmation in a few [46,47,54]. Among these HD cases with concomitant ALS, a single case had an additional pathogenic alteration in the ALS-associated VCP gene [54]; C9orf72 repeat expansion was negative for another case [47]. Rarely, C9orf72 repeat expansion has been shown to coexist with pathogenic alterations in other neurodegenerative-related genes such as MAPT, GRN, TARDBP, SOD1, OPTN, and TBK1 [56][57][58][59][60][61][62][63][64], suggesting that identification of a C9orf72 repeat expansion should not preclude testing for other neurodegenerative-related genes [65] and that C9orf72 and HTT repeat expansion coexistence is theoretically possible.…”

Section: Introductionmentioning

confidence: 99%

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C9orf72 Repeat Expansion Frequency among Patients with Huntington Disease Genetic Testing

et al. 2018

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Background: European studies identified the C9orf72 repeat expansion as the most frequent genetic alteration in patients with Huntington disease (HD)-like phenotypes but negative HD genetic testing. Objective: To investigate C9orf72 repeat expansion frequency in individuals tested for HD in a North American tertiary referral laboratory. Methods: Three hundred and seventy-three cases (115 positive and 258 negative for HD) were evaluated by genotyping PCR, with follow-up Southern blot and 5′ repeat methylation status assessment by combined repeat-primed and methylation-specific PCR in a subset. Results: Three cases (all HD-negative) tested positive: 2 had > 2,000 repeats and were methylated, 1 had 80–100 repeats and was unmethylated. Two cases (1 HD-positive and 1 HD-negative) had intermediate alleles (20–29 repeats) and were unmethylated. The remaining 368 cases were negative (< 20 repeats). C9orf72 repeat expansion was absent in patients with HD and was identified in a small subset (1.2%) of patients with negative HD genetic testing. Conclusion: These findings suggest that C9orf72 repeat expansion does not coexist with HTT repeat expansion and that C9orf72 repeat expansion testing is unnecessary for patients with HD. In addition, C9orf72 evaluation may be considered for individuals negative for HD genetic testing. Similar to in previous studies, methylation of C9orf72 repeat expansion was limited to large expansions.

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“…Na maioria dos casos a doença está na sua forma esporádica, mas 10% dos casos apresentam a forma familiar (ELAf) onde são causados por mutações no gene que codifica a enzima antioxidante citosólica (OSKARSSON et al, 2014), enquanto que a doença de Huntington é um distúrbio neurológico hereditário causada por uma mutação no cromossomo 4. Trata-se de uma doença autossômica dominante.…”

Section: Metodologiaunclassified

Efeito Protetor Do Resveratrol Na Doença De Alzheimer

Rosa

Machado

Frusciante

et al. 2017

RBM

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ResumoA Doença de Alzheimer (DA) é uma doença neurodegenerativa e progressiva, caracterizada por alterações comportamentais e cognitivas, apresenta como principais características neuropatológicas a presença de placas senis e emaranhados neurofibrilares. A presença de placas senis está relacionada com o metabolismo anormal da proteína precursora de amiloide (APP) e os emaranhados neurofibrilares são formados a partir da hiperfosforilação da proteína tau. O resveratrol, um potente antioxidante pertencente à família dos estilbenos, parece atuar como fator protetor na neurodegeneração da DA. O presente estudo tem como objetivo realizar uma revisão da literatura sobre o efeito protetor do resveratrol na DA, uma vez que não existe um tratamento efetivo para esta doença, portanto se necessita de uma busca de substâncias que poderiam ser adjuvantes terapêuticos nesta patologia. Palavras-chave:Resveratrol; Doença de Alzheimer; Antioxidantes. Protective Effect Of Resveratrol In Alzheimer's Disease AbstractAlzheimer's Disease (AD) is a neurodegenerative and progressive disease characterized by behavioral and cognitive changes and presents as major neuropathological features the presence of senile plaques and neurofibrillary tangles. The presence of senile plaques is related to the abnormal metabolism of amyloid precursor protein (APP) and neurofibrillary tangles are formed from hyperphosphorylation of tau protein.Resveratrol, a potent antioxidant belonging to the family of stilbenes, seems to act as a protective factor in the neurodegeneration of AD. The present study aims to conduct a literature review on the protective effect of resveratrol in AD, since there is no effective treatment for this disease, so there is anecessity to search for substances that could be therapeutic adjuvants in this pathology. Keywords: Resveratrol; Alzheimer's disease; Antioxidants IntroduçãoA Doença de Alzheimer (DA) é reconhecida atualmente como uma das formas mais comuns de demência em todo o mundo. Nos países desenvolvidos aproximadamente uma em cada dez pessoas acima dos 65 anos sofre de uma forma de demência, números que aumentam para mais de um terço naqueles acima dos 85 anos (POVOVA et al., 2012). Embora as causas da DA ainda sejam debatidas, duas características patológicas são cruciais no diagnóstico da doença, são elas: a presença de placas senis e os emaranhados neurofibrilares, sendo que estes últimos são formados pela hiperfosforilação da proteína tau (CRESPO et al., 2014). Agentes infecciosos, metais como alumínio e zinco, espécies reativas de oxigênio e proteínas associados também apresentam relação com o surgimento da DA (BOLOGNIN et al., 2013;FROZZA et al., 2013). A procura de abordagens terapêuticas da doença focou-se em compostos que têm como alvo as vias das proteínas β-amiloide e da proteína tau, a neuroinflamação e o dano oxidativo (HONG-QI et al., 2012). Entretanto, até o momento só existem tratamentos paliativos para a doença, logo,a busca por novas terapias e adjuvantes terapêuticos tem sido alvo de diversas pesqu...

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A case of familial ALS due to multi-system proteinopathy 1 and Huntington disease

Cited by 7 publications

References 9 publications

Detection of TDP‐43 oligomers in frontotemporal lobar degeneration–TDP

Detection of TDP‐43 oligomers in frontotemporal lobar degeneration–TDP

C9orf72 Repeat Expansion Frequency among Patients with Huntington Disease Genetic Testing

Efeito Protetor Do Resveratrol Na Doença De Alzheimer

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