Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that mainly affects both upper and lower motor neurons, accompanied by motor symptoms (Taylor et al., 2016). Cytoplasmic accumulation of TDP-43 in motor neurons is the most prominent pathological feature in ALS, which results in impaired protein quality control, mitochondrial dysfunction, and altered stress granule dynamics (Shahheydari et al., 2017; Davis et al., 2018; McDonald et al., 2011). This cytoplasmic accumulation often accompanies depletion of TDP-43 in the nucleus (Neumann et al., 2006), which then results in the loss of its nuclear functions including mRNA splicing (Highley et al., 2014) and the regulation of transcription (Amlie-Wolf et al., 2015). In addition to its occurrence in ALS, the cytoplasmic accumulation of TDP-43 in neurons is also observed in frontotemporal dementia (FTD; about 50% of patients) (Neumann et al., 2006), as well as in Alzheimer’s (Amador-Ortiz et al., 2007), Parkinson’s (Nakashima-Yasuda et al., 2007), and Huntington’s diseases (Schwab et al., 2008), although with lower frequency compared to ALS. These data suggest the importance of proper nucleocytoplasmic localization of TDP-43 for neuronal function.

TDP-43 is known to localize mainly in the nucleus of most neurons examined in non-pathological conditions (Diaper et al., 2013; Neumann et al., 2006; Uchino et al., 2015). Post-translational modifications (PTMs), such as ubiquitination and phosphorylation, and fragmentation of TDP-43 were shown to affect interactions among TDP-43 protein themselves and between TDP-43 and Importins, thereby promoting cytoplasmic accumulation of TDP-43 under pathological conditions including ALS (Neumann et al., 2006; Nonaka et al., 2009). Consistent with these findings, recently, a feedback cycle between nucleocytoplasmic transport (NCT) defect and TDP-43 aggregation was proposed as a model to explain cytoplasmic accumulation of TDP-43 in ALS conditions (Solomon et al., 2018; Gasset-Rosa et al., 2019). In this model, aggregation of TDP-43 in the cytoplasm captures the components (e.g., Importins) of NCT, causing NCT defects and reduced translocation of TDP-43 to the nucleus. These defects increase the amount of TDP-43 in the cytoplasm, which further accelerates cytoplasmic aggregation of TDP-43. Although this model explains the late stages of the disease very well, it remains unclear how this feedback cycle is initiated at the early stages or what predisposes neurons to be vulnerable to this feedback cycle.

Of note, TDP-43 has a property of shuttling between the nucleus and the cytoplasm in neurons under non-pathological conditions, and several factors have been shown to contribute to its NCT. Numerous studies have demonstrated contributions of nuclear transport machineries to NCT of TDP-43, including Importins (Importin α2, α3, and β1) (Nishimura et al., 2010; Solomon et al., 2018), RanGAP (Chou et al., 2018), and components of nuclear pore complexes (Nup62 and Nup54) (Nishimura et al., 2010). The signal sequences for NCT of TDP-43 have been reported: the nuclear localization signal (NLS) of TDP-43 was first identified in both cultured neurons and mouse brains, and its deletion resulted in cytoplasmic accumulation of TDP-43 (Winton et al., 2008). In contrast, deletion of a computationally predicted, leucine-rich nuclear export signal (NES) located at amino acids 239–250 in human TDP-43 (Winton et al., 2008) showed no significant effects on translocation of TDP-43 towards the cytoplasm in neurons (Pinarbasi et al., 2018).

Given that TDP-43 has distinct cytoplasmic functions in addition to its nuclear functions, TDP-43 localization can be dynamically changed (i.e. from nucleus to cytoplasm and vice versa) upon specific cellular demands for its location-specific functions. Although some specific pathological conditions, such as increased stress granule formation (Colombrita et al., 2009) or decreased autophagy (Nguyen et al., 2019), are known to induce cytoplasmic accumulation of TDP-43, it remains elusive whether there exist in neurons certain non-pathological cellular events in which the localization of TDP-43 shifts significantly from the nucleus to cytoplasm and vice versa. In this study, we found that TDP-43 shows cell-type-dependent variation in its localization and can undergo dynamic and reversible changes in its localization during development, one of the major cellular events, in Drosophila sensory neurons. Furthermore, we identify cytosolic calcium as a key cellular factor that controls nucleocytoplasmic localization of TDP-43 and establish the cytosolic calcium-Calpain-A-Importin α3 pathway as a molecular mechanism underlying NCT-mediated cytoplasmic accumulation of TDP-43 in Drosophila neurons.

In this study, we demonstrate a role of the calcium-CalpA-Imp α3 pathway in regulation of cytoplasmic accumulation of TDP-43. The involvement of this pathway further extends the previously proposed feedback cycle model (Solomon et al., 2018). In the previous model, amounts of cytoplasmic TDP-43 are increased through NCT defects caused by cytoplasmic aggregation of TDP-43, and increased levels of TDP-43 in the cytoplasm further accelerate TDP-43 aggregation. Our results provide an additional pathway that can increase the amounts of cytoplasmic TDP-43. How the calcium-CalpA-Imp α3 pathway interacts with the events in the feedback cycle model during progression of ALS is not certain. Interestingly, although modulation of cytosolic calcium levels led to reversible translocation of TDP-43 between the cytoplasm and the nucleus, TDP-43 aggregates were not observed in our study. Given this observation, the calcium-CalpA-Imp α3 pathway is likely to precede the sequestration of Importins by cytoplasmic TDP-43 aggregates and the subsequent NCT defects in the feedback cycle model. Therefore, our results provide an early regulatory mode to be therapeutically targeted for prevention of cytoplasmic accumulation of TDP-43 in ALS (Figure 7—figure supplement 1). In addition, we showed calcium-dependent dynamic changes of TDP-43 localization in neurons in response to the changes in cellular context during development. Together with a recent study showing shift in TDP-43 localization from nucleus to cytoplasm in skeletal muscle cells during regeneration (Vogler et al., 2018), our results suggest that translocation of TDP-43 is not necessarily pathological. This conclusion is supported by a recent study in which nuclear depletion and cytoplasmic accumulation of TDP-43 were observed in a subpopulation of neurons from various areas of healthy mouse brain (Termsarasab et al., 2020). These findings raise a new possibility that dynamic control of TDP-43 translocation can contribute to cytoplasmic accumulation of TDP-43 in ALS (Figure 7—figure supplement 2).

Among the candidate molecules selected from the genetic screen (Figure 4 and Figure 4—figure supplement 1), we focused on CalpA and Imp α3 during the search of the mechanism. However, in addition to CalpA and Imp α3, the candidate molecules also included two other calcium-dependent regulator candidates (Cam and Pkc53E) and four other nuclear import components (Imp α1, Imp β1, Imp 7, and Tnpo-SR). Cam acts as a nuclear transporter of sex-determining region Y (SRY), independent of Importin (Kaur et al., 2010). However, Cam was excluded from the following experiments because of no Cam-binding site in TBPH, as well as the lethality induced by its overexpression. In contrast, Pkc53E regulates nucleocytoplasmic localization of diacylglycerol kinase ζ (Topham et al., 1998) and ribosomal protein S6 kinase (S6K) by inhibiting functions of their NLSs via phosphorylation (Valovka et al., 2003). Pkc53E showed a comparable effect to CalpA on the localization of TBPH (Figure 4C). These data suggest the existence of an additional, Pkc53E-dependent pathway to regulate TBPH localization. Imp αs are known to form heterodimers with Imp βs (Moroianu et al., 1995, Jäkel et al., 1999) , suggesting that Imp α3 and Imp β1 may form a heterodimer to participate in our pathway. Indeed, disrupting this pathway via reducing CalpA level appears to interfere with nuclear translocation of another NLS-bearing protein, polyQ (MJDtr-78Q; Figure 7—figure supplement 3A), which is known to be transported via Imp α3 (Sowa et al., 2018). Notably, a reduction in CalpA mitigated polyQ-induced retinal degeneration (Figure 7—figure supplement 3B). These data suggest that calcium-mediated CalpA activity may affect nuclear localization of a broad range of proteins via Imp α3.

Calpains have been associated with neurotoxicity in a number of diseases including ALS (Vosler et al., 2008). There are 15 genes encoding calpains in mammals (Evans and Turner, 2007), among which Calpain-1 and −2 are most studied. In Neuro2a cells and in motor cortex of patients with frontotemporal lobar degeneration with clinical features of motor neuron disease (FTLD-MND), Yamashita et al., 2012 showed that Calpain-1 and −2 are responsible for the calcium-mediated cleavage of TDP-43, leading to its toxic accumulation in the cytoplasm. Calpain-mediated cleavage of TDP-43 into CTF-25 and CTF-35 during traumatic brain injury in mice has also been reported (Yang et al., 2014). In Drosophila, CalpA is most similar to Calpain-9 (Thurmond et al., 2019). Therefore, some of the functions of Calpain-1 and −2, such as cleavage of TDP-43, may not be conserved in CalpA. To test whether CalpA used in this study can also cleave TBPH, we overexpressed CalpA in fly heads and measured the amount and size of TBPH via western blot and compared them to the control. We found that CalpA overexpression led to no apparent pattern of TBPH cleavage on the blot (Figure 7—figure supplement 4A and B), although unexpectedly, it led to an increase in the amount of TBPH. Instead, we showed that CalpA is necessary for nuclear import of TBPH (Figure 4B and C) through a yet undefined mechanism. These data suggest that CalpA, unlike Calpain-1 and −2, does not cleave TBPH and instead may be protective against TBPH-mediated toxicity.

Knockdown of CalpA blocked nuclear translocation of Imp α3 in pupal C4da neurons (Figure 5A and B), suggesting that CalpA functions as an upstream regulator of Imp α3. A specific mechanism by which CalpA regulates TBPH translocation through Imp α3 remains to be shown. Calpain, a human orthologue of CalpA, is a protease with a broad spectrum of substrates (DuVerle et al., 2011). However, Importin α3, a human orthologue of Imp α3, has not been reported as a substrate of Calpain, nor predicted using the Calpain cleavage detector (CCD) software (Liu et al., 2011). These data suggest the possibility that CalpA regulates nuclear translocation of Imp α3 indirectly via its another target protein associated with nuclear import or export of Imp α3. Further functional study is needed to test the validity of this hypothesis.

Based on our data, Imp α3/β1 complex is the major transport regulator for nuclear import of TBPH (Figure 4—figure supplement 2A and B). Interestingly, knockdown of Imp α1, Tnpo-SR, and Imp seven also led to a significant shift in TBPH localization from the nucleus to the cytoplasm in pupae. TDP-43 has been shown to interact with both KPNA4 and KPNA6, the orthologs for which are Imp α3 and Imp α1, respectively (Nishimura et al., 2010). Interestingly, ectopic expression of Imp α1 in Drosophila eyes rescued glassy-eye phenotype of Imp α3 mutant (Mason et al., 2003), suggesting that Imp α1 and Imp α3 have somewhat redundant functions. Thus, it is not surprising that knockdown of Imp α1 also disrupted nuclear transport of TBPH. Whether Imp α1 also receives regulation from CalpA remains to be shown. As for Imp7 and Tnpo-SR, they both function at the upstream of mRNA splicing. Imp7 binds directly to small nuclear ribonucleoproteins (snRNPs), which are indispensable constituents of a spliceosome, and localizes them into Cajal bodies (Natalizio and Matera, 2013). Now, spliceosome assembly is also mediated by serine/arginine-rich splicing factor 1 (SRSF1) (Cho et al., 2011), which is transported into the nucleus by Tnpo-SR (Allemand et al., 2002). Notably, 517 and 333 SRSF1-regulated alternative splicing events were identified in 3D MCF-10A acini and HeLa cells, respectively (Anczuków et al., 2015). We surmise that knockdown of Imp7 and Tnpo-SR may cause widespread changes in alternative splicing, the result of which may impede TBPH import into the nucleus.

We reported in this study that TBPH localization shifts from the cytoplasm (at larval period) to the nucleus (at pupal period), but for what reason TBPH translocates into the nucleus during the pupal stage remains unknown. Interestingly, a previous study (Vanden Broeck et al., 2013) showed that loss of function of TBPH leads to increased Map205 expression, resulting in cytoplasmic mis-localization of ecdysone receptor-A (EcR-A), an isoform of EcR expressed predominantly during the late stages of pupa. These results raise a possibility that in C4da neurons, TBPH translocates into the nucleus during pupal stage to regulate the expression of Map205 and thus the nuclear localization of EcR-A, an important step for proper metamorphosis. Of note, several previous studies showed that the loss of liver X receptor β (LXRβ), a mammalian ortholog of EcR, results in motor neuron degeneration (Andersson et al., 2005; Bigini et al., 2010) and that LXRβ physically interacts with TDP-43 (Vanden Broeck et al., 2013). Another previous study showed that LXRβ links β-sitosterol to ALS-parkinsonism dementia complex (Kim et al., 2008). Furthermore, single-nucleotide polymorphisms (SNPs) for LXRβ were recently identified to be associated with the age of onset in ALS patients (Mouzat et al., 2018). These studies strongly suggest that disrupted LXRβ (EcR) signaling pathway may be associated with motor neuron diseases such as ALS. Taken together, it seems possible that neurons dynamically control the nucleocytoplasmic translocation of TDP-43 upon specific cellular demands such as regulation of LXRβ signaling associated with ALS pathogenesis.

Previous studies reported that increased calcium was observed in motor neurons of ALS mouse models (von Lewinski and Keller, 2005). Together with the fact that excessive intracellular calcium over the manageable capacity is able to trigger cell death, these observations support the idea that decreasing calcium can be an effective strategy to treat ALS. Consistent with this idea, riluzole, the FDA-approved medication for ALS, appears to delay the disease progression for 3 months by inhibiting calcium-mediated excitotoxicity. However, in a recent post-hoc study, the beneficial effect of riluzole was shown to be evident at late stage of ALS (stage 4), but not at earlier stages (stages 2 and 3) (Fang et al., 2018). Consistent with this post-hoc study, a previous study suggested that early intrinsic hyperexcitability may not contribute to motor neuron degeneration in ALS (Leroy et al., 2014). Moreover, a potentially protective function of calcium in motor neurons of ALS models at their early developmental stages has been reported (Saxena et al., 2013; Armstrong and Drapeau, 2013). Taken together, these findings suggest a possibility that intracellular calcium may have a concentration-dependent shift in its net effect on ALS pathogenesis from being protective to pathogenic as disease progresses. Our finding of the calcium-CalpA-Imp α3 pathway may provide a mechanistic insight to understand the role of calcium in ALS pathogenesis.

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Jeong Hyang Park

   1. Department of Brain & Cognitive Sciences, DGIST, Daegu, Republic of Korea
   2. Protein dynamics-based proteotoxicity control laboratory, Basic research lab, DGIST, Daegu, Republic of Korea

   Contribution

   Conceptualization, Resources, Formal analysis, Investigation, Visualization, Writing - original draft, Writing - review and editing

   Contributed equally with

   Chang Geon Chung

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7392-8366

2. Chang Geon Chung

   1. Department of Brain & Cognitive Sciences, DGIST, Daegu, Republic of Korea
   2. Protein dynamics-based proteotoxicity control laboratory, Basic research lab, DGIST, Daegu, Republic of Korea

   Contribution

   Conceptualization, Resources, Formal analysis, Investigation, Visualization, Writing - original draft, Writing - review and editing

   Contributed equally with

   Jeong Hyang Park

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8155-4926

3. Sung Soon Park

   1. Department of Brain & Cognitive Sciences, DGIST, Daegu, Republic of Korea
   2. Protein dynamics-based proteotoxicity control laboratory, Basic research lab, DGIST, Daegu, Republic of Korea

   Contribution

   Formal analysis, Investigation, Visualization, Writing - original draft

   Competing interests

   No competing interests declared

4. Davin Lee

   1. Department of Brain & Cognitive Sciences, DGIST, Daegu, Republic of Korea
   2. Protein dynamics-based proteotoxicity control laboratory, Basic research lab, DGIST, Daegu, Republic of Korea

   Contribution

   Formal analysis, Investigation, Visualization, Writing - original draft

   Competing interests

   No competing interests declared

5. Kyung Min Kim

   1. Department of Brain & Cognitive Sciences, DGIST, Daegu, Republic of Korea
   2. School of Biological Sciences, Seoul National University, Seoul, Republic of Korea

   Contribution

   Formal analysis, Investigation, Visualization

   Competing interests

   No competing interests declared

6. Yeonjin Jeong

   1. Department of Brain & Cognitive Sciences, DGIST, Daegu, Republic of Korea
   2. Protein dynamics-based proteotoxicity control laboratory, Basic research lab, DGIST, Daegu, Republic of Korea

   Contribution

   Formal analysis, Visualization

   Competing interests

   No competing interests declared

7. Eun Seon Kim

   1. Department of Brain & Cognitive Sciences, DGIST, Daegu, Republic of Korea
   2. Dementia research group, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea

   Contribution

   Investigation

   Competing interests

   No competing interests declared

8. Jae Ho Cho

   1. Department of Brain & Cognitive Sciences, DGIST, Daegu, Republic of Korea
   2. Protein dynamics-based proteotoxicity control laboratory, Basic research lab, DGIST, Daegu, Republic of Korea

   Contribution

   Formal analysis

   Competing interests

   No competing interests declared

9. Yu-Mi Jeon

   Dementia research group, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea

   Contribution

   Investigation

   Competing interests

   No competing interests declared

10. C-K James Shen

    Taipei Medical University/Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan

    Contribution

    Resources

    Competing interests

    No competing interests declared

11. Hyung-Jun Kim

    Dementia research group, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea

    Contribution

    Investigation

    Competing interests

    No competing interests declared

12. Daehee Hwang

    School of Biological Sciences, Seoul National University, Seoul, Republic of Korea

    Contribution

    Conceptualization, Supervision, Funding acquisition, Writing - original draft, Writing - review and editing

    For correspondence

    daehee@snu.ac.kr

    Competing interests

    No competing interests declared

13. Sung Bae Lee

    1. Department of Brain & Cognitive Sciences, DGIST, Daegu, Republic of Korea
    2. Protein dynamics-based proteotoxicity control laboratory, Basic research lab, DGIST, Daegu, Republic of Korea
    3. Dementia research group, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea

    Contribution

    Conceptualization, Resources, Supervision, Funding acquisition, Writing - original draft, Writing - review and editing

    For correspondence

    sblee@dgist.ac.kr

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-8980-6769

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