Expression of mutant SOD1^G93A in astrocytes induces functional deficits in motoneuron mitochondria

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motoneuron degeneration resulting in paralysis and eventual death. ALS is regarded as a motoneuron‐specific disorder but increasing evidence indicates non‐neuronal cells play a significant role in disease pathogenesis. Although the precise aetiology of ALS remains unclear, mutations in the superoxide dismutase (SOD1) gene are known to account for approximately 20% of familial ALS. We examined the influence of SOD1G93A expression in astrocytes on mitochondrial homeostasis in motoneurons in a primary astrocyte : motoneuron co‐culture model. SOD1G93A expression in astrocytes induced changes in mitochondrial function of both SOD1G93A and wild‐type motoneurons. In the presence of SOD1G93A astrocytes, mitochondrial redox state of both wild‐type and SOD1G93A motoneurons was more reduced and mitochondrial membrane potential decreased. While intra‐mitochondrial calcium levels [Ca2+]m were elevated in SOD1G93A motoneurons, changes in mitochondrial function did not correlate with [Ca2+]m. Thus, expression of SOD1G93A in astrocytes directly alters mitochondrial function even in embryonic motoneurons, irrespective of genotype. These early deficits in mitochondrial function induced by surrounding astrocytes may increase the vulnerability of motoneurons to other neurotoxic mechanisms involved in ALS pathogenesis.

Molecular and Electrical Abnormalities in the Mouse Model of Amyotrophic Lateral Sclerosis

“…As these changes might suggest, there is a buildup of insoluble SOD1 proteins at this time (Johnston et al, 2000, Turner et al, 2003a, followed shortly by fragmentation of the Golgi (Mourelatos et al, 1996). The next signs of impairment appear in the mitochondria and in the cellular transport system (Zhang et al, 1997, Warita et al, 1999, Williamson and Cleveland, 1999, Mattiazzi et al, 2002, Kieran et al, 2005, Damiano et al, 2006, De Vos et al, 2007, Bilsland et al, 2008, Nguyen et al, 2009, Bilsland et al, 2010, Li et al, 2010. The immune response is initiated next (Alexianu et al, 2001, Chiu et al, 2008, Gowing et al, 2008, Chiu et al, 2009.…”

“…In addition, SOD1 mitochondria appear to be impaired in function under basal conditions (Mattiazzi et al, 2002, Nguyen et al, 2009, Li et al, 2010. Before the onset of symptoms, SOD1 mitochondria show decreased protein import, altered Ca 2+ sequestering, and an exaggerated response of the electrical gradient of the inner membrane to stimulation-induced Ca 2+ influx (Damiano et al, 2006, Bilsland et al, 2008, Nguyen et al, 2009, Li et al, 2010. By the time symptoms appear there is severe damage to mitochondrial membrane potentials, respiration, the electron transport chain and ATP synthesis (Mattiazzi et al, 2002, Jaiswal and).…”

“…As motoneurons mature they must cope with an everincreasing burden of Ca 2+ influx through voltage-gated Ca 2+ channels (as the Ca 2+ PIC increases with age) and SOD1 motoneurons have a heavier burden due to potentiation of the Ca 2+ PIC and altered AMPA receptors which are more Ca 2+ -permeable. 1 (Quinlan et al, 2011), 2 (Kuo et al, 2005), 3 (van Zundert et al, 2008), 4 (Meehan et al, 2010), 5 (Carunchio et al, 2010), 6 (Pieri et al, 2009), 7 (Bories et al, 2007), 8 (Amendola and Durand, 2008), 9 (Saxena et al, 2009), 10 (Johnston et al, 2000), 11 (Turner et al, 2003b), 12 (Mourelatos et al, 1996), 13 (Li et al, 2010), 14 (Jaiswal and Keller, 2009), 15 (Mattiazzi et al, 2002), 16 (Nguyen et al, 2009), 17 (Jaiswal et al, 2009), 18 (Bilsland et al, 2008), 19 (Damiano et al, 2006), 20 (Bilsland et al, 2010), 21 (De Vos et al, 2007), 22 (Williamson and Cleveland, 1999), 23 (Zhang et al, 1997), 24 (Kieran et al, 2005), 25 (Warita et al, 1999), 26 (Alexianu et al, 2001), 27 (Gowing et al, 2008), 28 (Chiu et al, 2008), 29 (Chiu et al, 2009), 30 …”

Calcium transporters and their role in the development of neuronal disease and neuronal damage

“…Increasing evidence suggests that mitochondrial dysfunction plays an important role in brain ageing and the pathogenesis of neurodegenerative diseases (Eckert et al 2012). Dysfunction of single enzyme complexes, production of reactive oxygen species (ROS), mitochondrial permeability transition pore opening (mPTP), enhanced apoptosis, and structural alterations of mitochondria are believed to be crucial for the onset and progression of neurodegenerative diseases (Bilsland et al 2008).…”

Neuroprotective Function of Cellular Prion Protein in a Mouse Model of Amyotrophic Lateral Sclerosis

“…[7][8][9][10] Expression of muSOD1 in non-neuronal cells was sufficient to induce cell death in nearby motor neurons lacking muSOD1. 11,12 Since an early decrease of prion protein (Prp) mRNA has been described in an ALS model, 13 loss of Prp function might contribute to the neurodegenerative process not only in prion diseases but also in ALS. A number of physiological functions have meanwhile been attributed to Prp, including antioxidative and anti-apoptotic properties and involvement in transmembrane signaling and cell adhesion.…”