International ISSN: 2471-0016 ICPJL

Clinical Pathology Journal
Mini Review
Volume 2 Issue 3 - 2016
SOD1 Pathology in ALS: TDP or not TDP that is the Question
Hortle E*, Don EK, Stoddart JJ, Radford R, Laird AS, Morsch M, Chung R and Cole NJ
Department of Biomedical Sciences, Macquarie University, Australia
Received: April 15, 2016 | Published: May 09, 2016

*Corresponding author: Elinor Hortle, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Ground Floor, 2 Technology Place, F10A Building, Macquarie University, NSW 2109, Australia, T: +61298502723; F: +61298502701; Email:

Citation: Hortle E, Don EK, Stoddart JJ, Radford R, Laird AS, et al. (2016) SOD1 Pathology in ALS: TDP or not TDP that is the Question. Int Clin Pathol J 2(3): 00038. DOI: 10.15406/icpjl.2016.02.00038


Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron disease with no cure. Patients experience degeneration of both upper and lower motor neurons, which leads to paralysis and eventual death, usually within 2-5 years of onset. Although ALS was first described in 1824, there remains a lack of a detailed understanding of the mechanisms that culminate in the progressive spread of ALS pathology and subsequent motor neuron loss. Current understanding highlights Cu/Zn superoxide dismutase (SOD1) and transitive response DNA binding protein 43kDa (TDP-43) proteopathies as two of the main pathologies observed in ALS. However, despite the similarities between the two, they have historically been studied in isolation. Here we consider the emerging body of evidence that suggests that the disease mechanisms of the two proteopathies may be linked. We discuss the possibility that insights might be gained from studying the interactions between the two pathologies, instead of continuing to examine them in isolation in order to truly understand ALS pathology.

Keywords: ALS; MND; SOD1; TDP-43; Pathology; Proteopathy


ALS: Amyotrophic Lateral Sclerosis; C9ORF72: Chromosome 9 Open Reading frame 72; FALS: Familiar ALS; FUS: Fused In Sarcoma; HEK293: Human Embryonic Kidney 293; SALS: Sporadic ALS; shRNA: Small Hairpin RNA; siRNA: Small Interfering RNA; SOD1: Cu/Zn Superoxide Dismutase; TDP-43: Transactive Response DNA Binding Protein 43 kDa; VHL: Von Hippel Lindau


Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, with no cure, that affects both the upper and lower motor neurons. ALS patients experience muscle weakness that starts focally, but spreads, culminating in paralysis and in most cases death 2-5 years after diagnosis [1]. Currently we do not have a detailed understanding of what triggers ALS, or the mechanisms responsible for the progressive spreading of ALS pathology. The majority of cases are sporadic (SALS), occurring with no known genetic cause; around 10% of cases are familiarly inherited (FALS). Mutations in over 33 genes have been found to cause ALS [2-4], notably C9ORF72, FUS, TARDBP (which encodes TDP-43) and Cu/Zn superoxide dismutase (SOD1) [5-8].

A key pathological hallmark of ALS-including in those patients with no known genetic cause - is the aggregation of ubiquitinated proteins in brain and spinal cord neurons. In 2006 TDP-43 was identified as a major component of ubiquitinated inclusions in FTLD and ALS cases [9,10]. In the majority of cases (all SALS patients and most SOD-1-negative FALS patients, but not in SOD1 related ALS [11,12] these aggregates (also known as inclusions) consist largely of TDP-43. TDP-43 and SOD1 proteopathies have previously been considered to represent separate parts of the same spectrum of the disease, largely because TDP-43 inclusions have not been observed in SOD1 FALS cases [11,13,14], and early studies did not detect SOD1 in SALS protein inclusions [15]. Therefore, most research focuses on either TDP-43 or SOD1 pathology separately, and very little examines the effect that each may have on the other. Now, a new body of literature is emerging suggesting that TDP-43 dysregulation may induce SOD1 pathology, and that the two may be linked.


SOD1 is a detoxification enzyme localized to the cytoplasm and outer mitochondrial membrane, where it converts superoxide to hydrogen peroxide. In SOD1 FALS and SOD1 SALS cases (about 5% of ALS cases), inclusions containing mutant protein are observed in both astrocytes and neurons [15,16]. Although the precise cause of SOD1 aggregation has not been elucidated, many studies have implicated molecular chaperones in this process [17-19]. SOD1 transgenic rodents-expressing human FALS associated SOD1 mutations-have been extensively studied, and recapitulate many features of ALS, including axonal and mitochondrial dysfunction, progressive neuromuscular dysfunction, gliosis, motor neuron loss, and the formation of neuronal protein inclusions containing mutant SOD1 [20].

TDP-43 is a primarily nuclear localised transcription repressor that functions in RNA metabolism, splicing and translational regulation [21]. Briefly 97% of ALS cases [9] - including those with and without mutations in TARDBP - display characteristic pathology in neurons and glial cells: mislocalisation and accumulation of dense, insoluble aggregates containing phosphorylated TDP-43 in the cytoplasm. Numerous animal models both of TDP-43 over- and under-expression have been described [20,21]. One recent model, in which mice express a form of cytoplasmic human TDP-43, recapitulates several of the features of ALS, including cytoplasmic TDP-43 aggregation, nuclear clearance of mouse TDP-43, brain atrophy, muscle denervation, motor neuron loss, and progressive motor impairment leading to death [22].

SOD1 and TDP-43; are they connected?

Despite the fact that SOD1 and TDP-43 proteins have very different roles within the cell, there are marked similarities between the two resulting proteopathies. For example, both mutant SOD1 and mutant TDP-43 are able to induce misfolding and aggregation of their respective wild-type (wt) proteins [23,24]. Both are able to spread misfolded and toxic protein from cell to cell [14,23,25-30]. Both have been shown to induce motor neuron death in a non-cell autonomous fashion; that is, when mutant protein is introduced to astrocytes in mixed cultures or in vivo models, these astrocytes can then induce selective motor neuron death [31,32] (although this finding for TDP-43 is contested [33]).

A small number of studies have suggested that SOD1 pathology may be relevant to all ALS cases; not just the 5% with known mutations in SOD1. Some have detected misfolded wild-type SOD1 in both non-SOD1 FALS, as well as SALS patients [34-37], suggesting that SOD1 mutations are not required for the formation of SOD1 pathology. Similarly, in mixed primary cell cultures derived from both FALS and SALS patients, shRNA knockdown of wild-type SOD1 resulted in protection of motor neurons, in the absence of any previously reported disease variants in SOD1, FUS or TDP-43 [38], supporting early hypotheses that treating SOD1 pathology may be beneficial in all ALS cases, regardless of mutation status [39].

A direct connection between SOD1 and TDP-43 proteopathies has also been suggested by several in vitro studies. Somalinga et al. [40] showed that in HeLa TetOn cells, the amount of soluble SOD1 was increase by siRNA knockdown of TDP-43, and decreased by TDP-43 over-expression [40], suggesting TDP-43 can regulate the expression of SOD1. Xia et al showed that in both human embryonic kidney 293 (HEK293) cells and mouse neuroblastoma cells, knockdown of TDP-43 impaired SOD1 aggresome formation, resulting in a higher number of smaller SOD1 aggregates within the cell [41]. Similarly, Uchida et al. found that in HEK293 cells loss of TDP-43 could lead to an increase in von Hippel Lindau (VHL) protein levels, and that VHL overexpression increased the number of inclusion harbouring mutant SOD1 cells [42]. Together these studies suggest that TDP-43 can induce SOD1 pathology (although it is unclear whether changes to the number or size of SOD1 inclusions results in increased toxicity).

Perhaps the most intriguing evidence of a connection between SOD1, TDP-43 and the spreading of ALS pathology, comes from two recent studies by Pokrishevsky et al. [43], who were able to show that in mouse primary spinal cord cultures, transfection of both wild-type TDP-43, as well as TDP-43 carrying disease linked mutations, induced misfolding of wild-type SOD1. Moreover, they demonstrated that this aberrant SOD1 protein could propagate from cell-to-cell via conditioned media, and seed cytotoxic misfolding of wild-type SOD1 in the recipient cells. Interestingly, in this system, no transmission of TDP-43 pathology was observed [35,43] as previously reported in other systems [14].

Some caveats

The studies listed above suggest a connection between SOD1 and TDP43 proteopathies in ALS, but further work is required before they can be deemed conclusive. It is not yet clear whether misfolded wild-type SOD1 really is present in non-SOD1 ALS cases. Some studies have found no mutant or misfolded SOD1 in samples from non-SOD1 FALS and SALS patients [44-46]. Some have suggested that this discrepancy may be due to the different affinities of the various antibodies used in these experiments; an ‘inferior’ antibody may fail to detect misfolded SOD1, even if it is present [45]. However, given that even when using the same antibody, some studies have detected misfolded SOD134, and others have not [46], the finding remains unclear.

Most of the in vitro studies listed here propose that TDP-43 pathology is upstream of, and induces, SOD1 pathology. However, there is some evidence that the reverse may also be true: the accumulation of ubiquitinated TDP-43 has been detected in both humans and mice carrying SOD1 mutations [47,48]. In these cases, SOD1 pathology is presumably inducing TDP-43 pathology. Given the small number of studies conducted to date, it is difficult to conclude which of these alternatives is most relevant to human disease.

The ability to draw conclusions about the role of TDP-43 in inducing SOD1 pathology is also hampered by our lack of understanding of the effect of TDP-43 in disease. Both over- and under-expression of wild-type and mutant TDP-43 can induce ALS-like phenotypes in animal models20; equally, over-expression of the truncated C- terminal fragment can induce an ALS phenotype, without changes to the abundance of full length TDP-43 protein [49]. This lack of clarity has, in some cases, led to confusion within the literature. For example, both Xia et al and Cheng et al tested the effect of rapamycin on their respective drosophila models of TDP-43 induced ALS. While Xia et al. [41] found that rapamycin worsened ALS symptoms, Cheng et al found that it alleviated ALS symptoms [41,50]. This apparent contradiction can perhaps be explained by the fact that the former were knocking down TDP-43 to induce an ALS-like phenotype, and the latter were over-expressing TDP-43 to achieve the same effect. Therefore, it is difficult to directly relate the above mentioned knock-down and over expression models to human biology, and each study has to be considered in its own context.


The hypothesis that TDP-43 and SOD1 pathology are linked through the propagation of misfolded protein is yet to be confirmed, but is a promising avenue for further research. More than twenty years of studying TDP-43 and SOD1 in isolation has yielded key insights into the cellular and molecular pathology of ALS, but an unfortunate lack of translational findings from the lab to the clinic [51,52]. It has recently become clear that the pathogenesis of ALS is converging on two linked pathways - RNA processing and protein homeostasis-suggesting that there are conserved pathological mechanisms in this genetically heterogeneous disease [9,12]. As more evidence is compiled towards this hypothesis, it is becoming increasingly important to study the pathogenesis of ALS in the context of linked disease mechanisms. In order to understand the true pathological mechanism of this disease, it is of great importance to study the interactions between all ALS pathologies, instead of continuing to examine these proteopathies in isolation.

We are in an exciting time for ALS and neurodegenerative disease research. As the pace of discovery accelerates, it is important to keep an open mind. In vivo models may prove to be key in resolving the interactions between currently known genes, proteins, and mechanisms. All information that can add to our knowledge of the biology of ALS is critical to ending forever the slings and arrows of this devastating disease. It is clear that SOD1 and TDP-43 are key players in ALS; recent and future discovery of new genes to the ALS stage can only help us understand whether there is a divergence or a convergence of TDP-43 and SOD1 mechanisms in ALS.


We would like to thank The Snow Foundation, The Rebecca Cooper Medical Research Foundation and for their funding. Dr Nicholas Cole is supported by the National Health and Medical Research Council (NHMRC), project grant [GNT1034816], and Macquarie University. Dr Angela Laird is supported by the National Health and Medical Research Council (NHMRC), project grant (GNT1069235) and the Machado Joseph Disease Foundation.


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