Altered Intracellular Localization of SOD1 in Leukocytes from Patients with Sporadic Amyotrophic Lateral Sclerosis

Cereda, Cristina; Leoni, Emanuela; Milani, Pamela; Pansarasa, Orietta; Mazzini, Giuliano; Guareschi, Stefania; Alvisi, Elena; Ghiroldi, Andrea; Diamanti, Luca; Bernuzzi, Stefano; Ceroni, Mauro; Cova, Emanuela

doi:10.1371/journal.pone.0075916

Cited by 36 publications

(50 citation statements)

References 45 publications

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“…This view has been challenged by studies reporting misfolded SOD1 accumulation in motor neurons [6, 19, 22, 53] and glia [18] of spinal cords as well as in PBMCs [11] and lymphocytes [27] from SALS patients. Neural precursor cell (NPC)- [29] or patient- [57] derived astrocytes, as well as NPC-derived oligodendrocyte progenitors [17] from both SOD1 mutant or sporadic ALS patients have been reported to be toxic to co-cultured normal motor neurons.…”

Section: Introductionmentioning

confidence: 99%

Misfolded SOD1 is not a primary component of sporadic ALS

et al. 2017

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A common feature of inherited and sporadic ALS is accumulation of abnormal proteinaceous inclusions in motor neurons and glia. SOD1 is the major protein component accumulating in patients with SOD1 mutations, as well as in mutant SOD1 mouse models. ALS-linked mutations of SOD1 have been shown to increase its propensity to misfold and/or aggregate. Antibodies specific for monomeric or misfolded SOD1 have detected misfolded SOD1 accumulating predominantly in spinal cord motor neurons of ALS patients with SOD1 mutations. We now use seven different conformationally-sensitive antibodies to misfolded human SOD1 (including novel high affinity antibodies currently in pre-clinical development) coupled with immunohistochemistry, immunofluorescence and immunoprecipitation to test for the presence of misfolded SOD1 in high quality human autopsy samples. Whereas misfolded SOD1 is readily detectable in samples from patients with SOD1 mutations, it is below detection limits for all of our measures in spinal cord and cortex tissues from patients with sporadic or non-SOD1 inherited ALS. The absence of evidence for accumulated misfolded SOD1 supports a conclusion that SOD1 misfolding is not a primary component of sporadic ALS.

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Section: Introductionmentioning

confidence: 99%

Misfolded SOD1 is not a primary component of sporadic ALS

et al. 2017

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“…Curiously, the SOD1 distribution allowed to distinguish two different categories of patients: the first group had perinuclear SOD1 aggregates and the second one higher nuclear SOD1. In addition, Cereda [26] observed that patients with more perinuclear SOD1 expressed a major amount of insoluble proteins while the other group, characterized by predominant nuclear SOD1, had especially soluble fractions. Eventually, the authors tested whether these findings had clinical correlates (see Table 1 for general characteristics of patient cohort).…”

Section: Sod1 Aggregationmentioning

confidence: 98%

“…Given that, the hypothesis was that wild-type SOD1, under many environmental triggers, became misfolded SOD1 with reduced antioxidant activity (loss of function) and acquired toxic property as mutant SOD1 has [25]. Cereda and co-workers [26] demonstrated a bigger total amount of SOD1 in PBMCs of SALS patients than in cells of healthy controls or Alzheimer patients [26]. Curiously, the SOD1 distribution allowed to distinguish two different categories of patients: the first group had perinuclear SOD1 aggregates and the second one higher nuclear SOD1.…”

Section: Sod1 Aggregationmentioning

confidence: 99%

“…Given the lack of data on this issue in ALS pathogenesis, Cereda's group [26] focused its attention on the modulation of SOD1 mRNA levels by post-transcriptional mechanisms, in particular via ELAV proteins. Considering that oxidative stress plays a critical role in sporadic ALS, and that it is a trigger of ELAV activation, by treating human neuroblastoma SH-SY5Y cells with 1 mM H 2 O 2 , a significant up-regulation of SOD1 mRNA levels was reported [47].…”

Section: Post-transcriptional Regulationmentioning

confidence: 99%

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SOD1, from Bench to Bed: New Role for the Oldest Protein Implicated in ALS

Diamanti¹,

Zucchi²,

Orietta³

et al. 2016

Update on Amyotrophic Lateral Sclerosis

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In , the first superoxide dismutase SOD mutation in amyotrophic lateral sclerosis ALS patients has been described by Rosen et al. successively, the scientific literature focused on the role of SOD in the pathogenesis of ALS. While a clear genetic scenario has been presented, heterogeneous data have been formulated regarding transcriptional and post-transcriptional regulation of SOD so far. In particular, the dilemma concerns the SOD protein expression, in the direction of a loss of function of the wild-type SOD or a toxic gain of function of the altered SOD , both in FALS mutant-SOD and in SALS misfolded-SOD . In this chapter, we focus on the evolution of scientific knowledge about SOD protein in ALS patients, reviewing in detail the results obtained using peripheral blood cells in this research field. To conclude, we propose a brief summary of the described clinical correlation and discuss the possible SOD implication as a biomarker of ALS.

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“…In fact, PBMCs share more than 80% of their transcriptomes with other tissues, including the central nervous system, and can be isolated easily from patients by venipuncture [26]. Previous studies demonstrated that PBMCs are a valid cell model to study ALS [26][27][28][29]. Based on this and on the new vision of ALS as a pathology affecting not only motor neurons exclusively but also other cell systems [30][31][32], we investigated the possible role of VAPB as a pathologic marker in PBMCs from patients with sALS.…”

Section: Introductionmentioning

confidence: 99%

VAPB ER-Aggregates, A Possible New Biomarker in ALS Pathology

Cadoni

Biggio

Arru

et al. 2020

Cells

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A point mutation (P56S) in the gene-encoding vesicle-associated membrane-protein-associated protein B (VAPB) leads to an autosomal-dominant form of amyotrophic lateral sclerosis (ALS), classified as ALS-8. The mutant VAPB is characterized by ER-associated aggregates that lead to a complete reorganization of ER structures. Growing evidences suggest VAPB involvement in ALS pathomechanisms. In fact, numerous studies demonstrated VAPB alteration also in sporadic ALS (sALS) and showed the presence of its aggregates when others ALS-related gene are mutant. Recently, the identification of new biomarkers in peripheral blood mononuclear cells (PBMCs) has been proposed as a good noninvasive option for studying ALS. Here, we evaluated VAPB as a possible ALS pathologic marker analyzing PBMCs of sALS patients. Immunofluorescence analysis (IFA) showed a peculiar pattern of VAPB aggregates in sALS, not evident in healthy control (HC) subjects and in Parkinson’s disease (PD) PBMCs. This specific pattern led us to suppose that VAPB could be misfolded in sALS. The data indirectly confirmed by flow cytometry assay (FCA) showed a reduction of VAPB fluorescent signals in sALS. However, our observations were not associated with the presence of a genetic mutation or altered gene expression of VAPB. Our study brings further evidences of the VAPB role in ALS as a diagnostic biomarker.

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Altered Intracellular Localization of SOD1 in Leukocytes from Patients with Sporadic Amyotrophic Lateral Sclerosis

Cited by 36 publications

References 45 publications

Misfolded SOD1 is not a primary component of sporadic ALS

Misfolded SOD1 is not a primary component of sporadic ALS

SOD1, from Bench to Bed: New Role for the Oldest Protein Implicated in ALS

VAPB ER-Aggregates, A Possible New Biomarker in ALS Pathology

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