Calcium dysregulation in amyotrophic lateral sclerosis

Explore the role of calcium homeostasis in ALS pathogenesis.

Basics in Amyotrophic Lateral Sclerosis (ALS)

ALS is an adult-onset neurodegenerative disease that is characterized by the selective death of motor neurons in the motor cortex, brainstem and spinal cord. The signs of upper (spasticity, dysphagia, dysarthria) and lower (atrophy and fasciculations) motor neuron degeneration cause progressive handicaps in everyday life and typically lead to death 3 to 5 years after symptom onset (Beghi et al., 2007). Thus, the diagnosis of ALS is a devastating diagnosis for every patient and their families. However, single populations of motor neurons, like the oculomotor neurons and the motor neurons of Onuf’s nucleus, which are involved in the control of micturition and defecation, are spared by the disease.

While the majority of ALS cases occur sporadically (sALS), approximately 5 to 10% of patients have positive familial histories (fALS) (Byrne et al., 2011, Siddique and Lalani 2002). Approximately 20% of fALS cases display mutations in the human copper-zinc superoxide dismutase 1 (hSOD1) gene. Recent efforts have identified various additional ALS-associated genes, including:

  • VAPB (vesicle-associated membrane protein-associated protein B) (Nishimura et al., 2004)
  • TDP-43 (tar DNA- binding protein 43) (Neumann et al., 2006)
  • FUS/TLS (fused in sarcoma/translated in liposarcoma) (Vance et al., 2009)
  • Optineurin (Maruyama et al., 2010)
  • VCP (valosin- containing protein) (Johnson et al., 2010, DeJesus-Hernandez et al., 2011a)
  • Ubiquilin 2 (Deng et al., 2011)
  • C9orf72 (chromosome 9 open reading frame 72) (DeJesus- Hernandez et al., 2011b, Renton et al., 2011)
  • Profilin 1 (Wu et al., 2012).

Role of excitotoxicity, CaBPs, mitochondria and ER in the pathophysiology of ALS

Several molecular pathways, including excitotoxicity, mitochondrial dysfunction, oxidative stress, apoptosisautophagy are involved in the pathophysiology of ALS (Ferraiuolo et al., 2011). The two central pathways, excitotoxicity and mitochondrial dysfunction, are described below.

Excitotoxicity has been shown to be mediated through calcium-permeable AMPA receptors (Carriedo et al., 1996, Rothstein et al., 1993, Rothstein and Kuncl 1995), which are generally expressed in motor neurons (Greig et al., 2000, Pieri et al., 2003a, Pieri et al., 2003b). Motor neurons exhibit increased vulnerability to AMPA receptor-mediated excitotoxicity (Carriedo et al., 2000, Saroff et al., 2000, Van Den Bosch et al., 2000), while N-methyl-D-aspartate (NMDA) receptors seem to only play a minor role in motor neuron degeneration (Carriedo et al., 1996, Ikonomidou et al., 1996, Delfs et al., 1997, Saroff et al., 2000). The presence of extracellular calcium is crucial for the induction of glutamate excitotoxicity (Carriedo et al., 1996, Van Den Bosch et al., 2000); however, calcium influx solely through voltage-gated calcium channels (VGCC) is not able to induce motor neuron death (Van Den Bosch et al., 2002).

Comparison of the motor neurons that are affected by ALS and the motor neurons that are spared has revealed a lower expression of calcium binding proteins (CaBP) in affected neurons (Alexianu et al., 1994, Ince et al., 1993, Siklos et al., 1998). Indeed, the overexpression of CaBP has neuroprotective effects in vitro and in vivo, delaying the disease onset and the survival of G93A hSOD1 mice (Beers et al., 2001, Roy et al., 1998). Nevertheless, the presence of only small amounts of  CaBP is most likely required for the high frequency activity of motor neurons and therewith a physiologic feature of motor neurons that are vulnerable to ALS (Lips and Keller 1998). Thus the most important key regulators of intracellular calcium homeostasis are likely to be mitochondria and the endoplasmic reticulum (ER). Mitochondria are able to rapidly take up large amounts of calcium via the mitochondrial uniporter (mUP) (Pivovarova and Andrews 2010), and the ER serves as a large calcium store (Berridge 2002). Indeed, it has been shown that mitochondria play a major role in the calcium buffering of motor neurons (Grosskreutz et al., 2007).

Mitochondrial dysfunction and ER stress are major pathophysiological mechanisms in ALS. Soon after the establishment of the G93A hSOD1 mouse model, mitochondria derived vacuoles were described (Dal Canto and Gurney 1994, Chiu et al., 1995). Swollen mitochondria were verifiable in G93A hSOD1 motor neurons as soon as two weeks of age, long before the first symptoms occur (Bendotti et al., 2001). These structural alterations of mitochondria have been confirmed in human sALS tissue (Sasaki and Iwata 2007). Functional deficits of mitochondria, i.e. in electron transport chain complexes have been found in sALS (Fujita et al., 1996, Borthwick et al., 1999) and mutated hSOD1 mice. These deficits became apparent in early symptomatic mice (Jung et al., 2002, Mattiazzi et al., 2002, Kirkinezos et al., 2005). Regarding the ER, morphological alterations, including dilatation and ribosomal detachment, have been observed in G93A hSOD1 mice (Dal Canto and Gurney 1994, Dal Canto and Gurney 1995) and in the spinal anterior horn cells of sALS patients (Oyanagi et al., 2008). Functional disturbances of the ER have recently been brought into focus, as induction of the unfolded protein response (UPR) has been shown in mutated hSOD1 mice (Tobisawa et al., 2003, Nagata et al., 2007) and in ALS patients (Atkin et al., 2008). In addition, an interaction of VAPB and TDP43 with mitochondria and ER has been recently shown and demonstrates the importance of ER–mitochondria associations in the pathophysiology of ALS (Stoica et al., 2014).


The dysfunction of neuronal calcium homeostasis plays a central role in neurodegenerative diseases. In ALS different cellular and molecular mechanisms of calcium dysregulation have been identified over the last 3 decades, however the causal relationship is still poorly understood. Basic research is much needed to unravel the contribution and principle mechanisms of calcium dysregulation.


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