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- Ohta, Yasuyuki, et al.
(författare)
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Sex-dependent effects of chromogranin B P413L allelic variant as disease modifier in amyotrophic lateral sclerosis
- 2016
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Ingår i: Human Molecular Genetics. - : OXFORD UNIV PRESS. - 0964-6906 .- 1460-2083. ; 25:21, s. 4771-4786
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Tidskriftsartikel (refereegranskat)abstract
- Recent genetic studies yielded conflicting results regarding a role for the variant chromogranin B (CHGB)(P413L) allele as a disease modifier in ALS. Moreover, potential deleterious effects of the CHG(BP413L) variant in ALS pathology have not been investigated. Here we report that in transfected cultured cells, the variant CHGB(L413) protein exhibited aberrant properties including mislocalization, failure to interact with mutant superoxide dismutase 1 (SOD1) and defective secretion. The CHGB(L413) transgene in SOD1(G37R) mice precipitated disease onset and pathological changes related to misfolded SOD1 specifically in female mice. However, the CHGB(L413) variant also slowed down disease progression in SOD1(G37R) mice, which is in line with a very slow disease progression that we report for a Swedish woman with ALS who is carrier of two mutant SOD1(D90A) alleles and two variant CHGB(P413)L and CHGB(R458Q) alleles. In contrast, overexpression of the common CHGB(P413) allele in SOD1(G37R) mice did not affect disease onset but significantly accelerated disease progression and pathological changes. As in transgenic mice, the CHGB(P413L) allele conferred an earlier ALS disease onset in women of Japanese and French Canadian origins with less effect in men. Evidence is presented that the sex-dependent effects of CHGB(L413) allelic variant in ALS may arise from enhanced neuronal expression of CHGB in females because of a sex-determining region Y element in the gene promoter. Thus, our results suggest that CHGB variants may act as modifiers of onset and progression in some ALS populations and especially in females because of higher expression levels compared to males.
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- Paré, Bastien, et al.
(författare)
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Misfolded SOD1 pathology in sporadic Amyotrophic Lateral Sclerosis
- 2018
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Aggregation of mutant superoxide dismutase 1 (SOD1) is a pathological hallmark of a subset of familial ALS patients. However, the possible role of misfolded wild type SOD1 in human ALS is highly debated. To ascertain whether or not misfolded SOD1 is a common pathological feature in non-SOD1 ALS, we performed a blinded histological and biochemical analysis of post mortem brain and spinal cord tissues from 19 sporadic ALS, compared with a SOD1 A4V patient as well as Alzheimer's disease (AD) and non-neurological controls. Multiple conformation-or misfolded-specific antibodies for human SOD1 were compared. These were generated independently by different research groups and were compared using standardized conditions. Five different misSOD1 staining patterns were found consistently in tissue sections from SALS cases and the SOD1 A4V patient, but were essentially absent in AD and non-neurological controls. We have established clear experimental protocols and provide specific guidelines for working, with conformational/misfolded SOD1-specific antibodies. Adherence to these guidelines will aid in the comparison of the results of future studies and better interpretation of staining patterns. This blinded, standardized and unbiased approach provides further support for a possible pathological role of misSOD1 in SALS.
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