All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration

Abstract

Multiple neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) are being suggested to have common cellular and molecular pathological mechanisms, characterized mainly by protein misfolding and aggregation. These large inclusions, most likely, represent an end stage of a molecular cascade; however, the soluble misfolded proteins, which take part in earlier steps of this cascade, are the more toxic players. These pathological proteins, which characterize each specific disease, lead to the selective vulnerability of different neurons, likely resulting from a combination of different intracellular mechanisms, including mitochondrial dysfunction, ER stress, proteasome inhibition, excitotoxicity, oxidative damage, defects in nucleocytoplasmic transport, defective axonal transport and neuroinflammation. Damage within these neurons is enhanced by damage from the nonneuronal cells, via inflammatory processes that accelerate the progression of these diseases. In this review, while acknowledging the hallmark proteins which characterize the most common NDDs; we place specific focus on the common overlapping mechanisms leading to disease pathology despite these different molecular players and discuss how this convergence may occur, with the ultimate hope that therapies effective in one disease may successfully translate to another.

Motor neuron-derived induced pluripotent stem cells as a drug screening platform for amyotrophic lateral sclerosis

“…iPSCs and co-cultures are potentially beneficial to incorporate critical controllers of neuronal health into ALS studies. This involvement of non-neuronal cell types is consistent with the non-cell-autonomous theory that challenges the cell-autonomous theory (Chen et al, 2018;Argueti-Ostrovsky et al, 2021).…”

Disruption of lactate metabolism in the peripheral nervous system leads to motor-selective deficits

“…A range of cellular processes are reported to influence liability for the most common motor neuron disease, ALS. These include aberrant RNA processing, ER stress, metabolic abnormalities, neuroinflammation, oxidative damage, and mitochondrial dysfunction, among others 61 . As with many neurodegenerative conditions, age is the primary risk factor for ALS, and there is clear overlap between pathways implicated in the disease and natural aging processes 62 .…”

Therapeutic Treatment of Superoxide Dismutase 1 (G93A) Amyotrophic Lateral Sclerosis Model Mice with Medical Ozone Decelerates Trigeminal Motor Neuron Degeneration, Attenuates Microglial Proliferation, and Preserves Monocyte Levels in Mesenteric Lymph Nodes

“…These vacuoles are most likely swollen mitochondria, with the involvement of aggregated mutant SOD1 for their appearance [ 20 , 21 , 38 ]. Since pathologic aggregation of proteins is considered a main reason for neurodegeneration in general [ 39 ], and SOD1-related neurodegeneration in ALS in particular [ 40 ], reductions in the severity of this process may be the underlying reason for our observed protection against trigeminal motor neuron loss. We also showed that MRI analysis of the trigeminal and facial motor nuclei recapitulated human SOD1-related vacuolization.…”