Age-Related Proteostasis Disturbance
During the aging process, a decline in the normal cellular ability to maintain proteostasis is observed and, as a result, damaged proteins accumulate (Kikis et al., 2010). Thus the normal aging process in MNs that are already weakened by ALS-associated insults, such as the presence of misfolded proteins or environmental factors, may combine to induce neurodegeneration. MN populations that are more susceptible in ALS may therefore be less able to tolerate disturbances in proteostasis than the more resistant populations (Neumann et al., 2006; Kikis et al., 2010).
Mitochondria play a crucial role in neuronal aging. Normal features observed in the aging brain include the accumulation of mutations in mitochondrial DNA, the production of ROS, mitochondrial metabolic abnormalities and altered Ca2+ storage (Sun et al., 2016). Remarkably, mitochondria in different regions of the CNS are not equally affected during aging. The sensitivity of the mitochondrial permeability transition pore to Ca2+ in the cortex and hippocampus is greater than that of the striatum and the cerebellum in aged rats (LaFrance et al., 2005; Brown et al., 2006). The cellular location of mitochondria is also relevant to the aging processes. Synaptic mitochondria are more prone to oxidative stress-induced damage than mitochondria located in the soma (Brown et al., 2006; Reddy and Beal, 2008). In addition, synaptic mitochondria display a limited capacity to accumulate Ca2+, unlike those located in the soma (Brown et al., 2006). Furthermore, marked differences have been described between mitochondria located in the spinal cord and those found in distal axons of MNs from aged rats. In the axon termini at the NMJ, mitochondria swelling, fusion and an abundance of megamitochondria (giant mitochondria) during aging have been reported (García et al., 2013). These studies therefore imply that mitochondria become dysfunctional in aged MNs, which might sensitize vulnerable MN populations to ALS/FTD. Mitochondria located at the synapse may also be particularly vulnerable to these age-related processes.