ALS/FTD: Evolution, Aging, and Cellular Metabolic Exhaustion

Abstract

Amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) are neurodegenerations with evolutionary underpinnings, expansive clinical presentations, and multiple genetic risk factors involving a complex network of pathways. This perspective considers the complex cellular pathology of aging motoneuronal and frontal/prefrontal cortical networks in the context of evolutionary, clinical, and biochemical features of the disease. We emphasize the importance of evolution in the development of the higher cortical function, within the influence of increasing lifespan. Particularly, the role of aging on the metabolic competence of delicately optimized neurons, age-related increased proteostatic costs, and specific genetic risk factors that gradually reduce the energy available for neuronal function leading to neuronal failure and disease.

History of ALS and the competing theories on pathogenesis: IFCN handbook chapter

“…The cascade of events that determine cellular senescence are poorly defined, but amongst other factors, a failing response to cellular energy demands ranks highly ( Henderson et al, 2022 ). Over time there is metabolic exhaustion of energy-demanding neocortical neurons ( Fig.…”

“…Aging and senescence impair energy balance in homeostasis. At a cellular level this increases the tendency to protein degradation, aggregation and mis-localization with subsequent development of neurodegeneration ( Henderson et al, 2022 ). …”

Nanoplastics and Neurodegeneration in ALS

“…Due to their post-mitotic nature, and inability to regenerate, neurons may be more vulnerable to cellular toxicity and are more ATP-dependent than other cells, making them more susceptible to energy crises associated with inflammation [87]. The neuroinflammatory cascade is activated by microglia and astrocytes and mediated by key pro-inflammatory cytokines (IL-1β, IL-6, and TNFα), which regulate adhesion molecule expression, cell growth, cell division, and apoptosis [88].…”

Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders

“…By contrast, NDD pathogenesis shows considerable overlap in protein misfolding and aggregation; defects in the endosomal-lysosomal network and the clearance of damaged proteins by autophagy or proteasomes; mitochondrial dysfunction and oxidative stress; inflammasome dysfunction; cellular calcium imbalance; impaired axonal, membrane, or nucleocytoplasmic trafficking; DNA damage response; and synaptic dysfunction, many of which crosstalk and are directly or indirectly linked to neuroinflammation and even systemic (peripheral) immune imbalance (Figure 1) [22][23][24][25][26][27][28][29][30][31][32][33]. Most of these mechanisms are also affected by ageing, the most prominent risk factor for adult-onset NDDs, which is, in the immune system, linked to immunosenescence, with increased activated adaptive immune cells and a decreased repertoire of naïve cells, and chronic low-grade inflammation [34,35]. In this chapter, we focus on overlapping proteinopathies and immune imbalance in NDDs, the two features that have recently been tackled for designing and monitoring efficient therapies.…”