Familial amyotrophic lateral sclerosis with Cys111Tyr mutation in Cu/Zn superoxide dismutase showing widespread Lewy body-like hyaline inclusions

Yasui, Kanako; Ishikawai, Hiroaki; Nomura, Makoto; Watanabe, Takeshi; Mikami, Hirotsugu; Yamano, T.; Ono, Seiitsu

doi:10.1016/j.jns.2010.09.007

Cited by 7 publications

(4 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The final mutation we identified, p.C111Y, has been identified in North American, Japanese and Chinese families. The most common initial symptoms were primarily located in the spinal cord, and the disease progressed relatively slowly3435. According to our results, all five of these mutations were located in exon 4, which appears to be a hotspot of variation in comparison to other exons.…”

Section: Discussionsupporting

confidence: 52%

Screening of SOD1, FUS and TARDBP genes in patients with amyotrophic lateral sclerosis in central-southern China

Hou

Jiao

Xiao

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons of the brain, brainstem and spinal cord. To date, mutations in more than 30 genes have been linked to the pathogenesis of ALS. Among them, SOD1, FUS and TARDBP are ranked as the three most common genes associated with ALS. However, no mutation analysis has been reported in central-southern China. In this study, we sequenced SOD1, FUS and TARDBP in a central-southern Chinese cohort of 173 patients with ALS (15 familial ALS and 158 sporadic ALS) to detect mutations. As a result, five missense mutations in SOD1, namely, p.D101N, p.D101G, p.C111Y, p.N86S and p.V87A, were identified in three unrelated familial probands and three sporadic cases; two mutations in FUS were found in two unrelated familial probands, including an insertion mutation (p.P525_Y526insY) and a missense mutation (p.R521H); no variants of TARDBP were observed in patients. Therefore, SOD1 mutations were present in 20.0% of familial ALS patients and 1.9% of sporadic ALS patients, while FUS mutations were responsible for 13.3% of familial ALS cases, and TARDBP mutations were rare in either familial or sporadic ALS cases. This study broadens the known mutational spectrum in patients with ALS and further demonstrates the necessity for genetic screening in ALS patients from central-southern China.

show abstract

Section: Discussionsupporting

confidence: 52%

Screening of SOD1, FUS and TARDBP genes in patients with amyotrophic lateral sclerosis in central-southern China

Hou

Jiao

Xiao

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…However, mice expressing transgenes to multiple different SOD1 mutations develop the ALS-characteristic spheroids composed of both pNF and INA [31]. It has been reported that Lewy body like inclusions or conglomerate inclusions can be observed in extramotor motor neurons in some SOD1 mutation cases, but these tend to be exceptional patients in terms of long disease duration due to aggressive ventilatory support [29,30,11]. In contrast, the proband and her daughter had disease of relatively short duration, implying that disease duration is unlikely to be a driving factor for their extensive extramotor pathology and more likely related to specific nature of the truncating SOD1 mutation itself.…”

Section: Discussionmentioning

confidence: 99%

A truncating SOD1 mutation, p.Gly141X, is associated with clinical and pathologic heterogeneity, including frontotemporal lobar degeneration

et al. 2015

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a degenerative disorder affecting upper and lower motor neurons, but it is increasingly recognized to affect other systems, with cognitive impairment resembling frontotemporal dementia (FTD) in some patients. We report clinical and pathologic findings of a family with ALS due to a truncating mutation, p.Gly141X, in copper/zinc superoxide dismutase (SOD1). The proband presented clinically with FTD and later showed progressive motor neuron disease, while all other family members had early-onset and rapidly progressive ALS without significant cognitive deficits. Pathologic examination of both the proband and her daughter revealed degeneration of corticospinal tracts and motor neurons in brain and spinal cord compatible with ALS. On the other hand, the proband also had neocortical and limbic system degeneration with pleomorphic neuronal cytoplasmic inclusions. Extramotor pathology in her daughter was relatively restricted to the hypothalamus and extrapyramidal system, but not the neocortex. The inclusions in the proband and her daughter were immunoreactive for SOD1, but negative for TAR DNA binding protein of 43 kDa (TDP-43). In the proband, a number of the neocortical inclusions were immunopositive for α-internexin, initially suggesting a diagnosis of atypical FTLD, but there was no evidence of fused in sarcoma (FUS) immunoreactivity, which is often detected in atypical FTLD. Analogous to atypical FTLD, neuronal inclusions had variable co-localization of SOD1 and α-internexin. The current classification of FTLD is based on the major constituent protein: FTLD-tau, FTLD-TDP-43, and FTLD-FUS. The proband in this family indicates that SOD1, while rare, can also be the substrate of FTLD, in addition to the more common presentation of ALS. The explanation for clinical and pathologic heterogeneity of SOD1 mutations, including the p.Gly141X mutation, remains unresolved.

show abstract

“…Its persistence in different phylogenetic groups however could point to a functional role, possibly environmental redox sensing (Go et al ., 2015). Cys111 is known to be a key modulator of SOD1 expression level, folding, stability, aggregation and toxicity (Jabusch et al ., 1980; Lepock et al ., 1990; Hallewell et al ., 1991; Suzuki et al ., 2011; Chen et al ., 2012; Zhang et al ., 2017). A potential mechanism for this may be found in the asymmetry and hydrogen bonding network of SOD1 loop VI within which Cys111 is found (Ihara et al ., 2012).…”

Section: Secondary Sod1 Post-translational Modificationsmentioning

confidence: 99%

The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis

Wright

Antonyuk

Hasnain

2019

Quart. Rev. Biophys.

View full text Add to dashboard Cite

Few proteins have come under such intense scrutiny as superoxide dismutase-1 (SOD1). For almost a century, scientists have dissected its form, function and then later its malfunction in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We now know SOD1 is a zinc and copper metalloenzyme that clears superoxide as part of our antioxidant defence and respiratory regulation systems. The possibility of reduced structural integrity was suggested by the first crystal structures of human SOD1 even before deleterious mutations in thesod1gene were linked to the ALS. This concept evolved in the intervening years as an impressive array of biophysical studies examined the characteristics of mutant SOD1 in great detail. We now recognise how ALS-related mutations perturb the SOD1 maturation processes, reduce its ability to fold and reduce its thermal stability and half-life. Mutant SOD1 is therefore predisposed to monomerisation, non-canonical self-interactions, the formation of small misfolded oligomers and ultimately accumulation in the tell-tale insoluble inclusions found within the neurons of ALS patients. We have also seen that several post-translational modifications could push wild-type SOD1 down this toxic pathway. Recently we have come to view ALS as a prion-like disease where both the symptoms, and indeed SOD1 misfolding itself, are transmitted to neighbouring cells. This raises the possibility of intervention after the initial disease presentation. Several small-molecule and biologic-based strategies have been devised which directly target the SOD1 molecule to change the behaviour thought to be responsible for ALS. Here we provide a comprehensive review of the many biophysical advances that sculpted our view of SOD1 biology and the recent work that aims to apply this knowledge for therapeutic outcomes in ALS.

show abstract

Familial amyotrophic lateral sclerosis with Cys111Tyr mutation in Cu/Zn superoxide dismutase showing widespread Lewy body-like hyaline inclusions

Cited by 7 publications

References 21 publications

Screening of SOD1, FUS and TARDBP genes in patients with amyotrophic lateral sclerosis in central-southern China

Screening of SOD1, FUS and TARDBP genes in patients with amyotrophic lateral sclerosis in central-southern China

A truncating SOD1 mutation, p.Gly141X, is associated with clinical and pathologic heterogeneity, including frontotemporal lobar degeneration

The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis

Contact Info

Product

Resources

About