Potential common pathogenesis of several neurodegenerative diseases

Abstract

With the gradual advancement of research methods and technologies, various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases. However, current descriptions of these biological processes do not fully explain the onset, progression, and development of these conditions. Therefore, exploration of the pathogenesis of neurodegenerative diseases remains a valuable area of research. This review summarizes the potential common pathogeneses of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, frontotemporal lobar dementia, and Lewy body disease. Research findings have indicated that several common biological processes, including aging, genetic factors, progressive neuronal dysfunction, neuronal death and apoptosis, protein misfolding and aggregation, neuroinflammation, mitochondrial dysfunction, axonal transport defects, and gut microbiota dysbiosis, are involved in the pathogenesis of these six neurodegenerative diseases. Based on current information derived from diverse areas of research, these biological processes may form complex pathogenic networks that lead to distinctive types of neuronal death in neurodegenerative diseases. Furthermore, promoting the regeneration of damaged neurons may be achievable through the repair of affected neural cells if the underlying pathogenesis can be prevented or reversed. Hence, these potential common biological processes may represent only very small, limited elements within numerous intricate pathogenic networks associated with neurodegenerative diseases. In clinical treatment, interfering with any single biological process has proven insufficient to completely halt the progression of neurodegenerative diseases. Therefore, future research on the pathogenesis of neurodegenerative diseases should focus on uncovering the complex pathogenic networks, rather than isolating individual biological processes. Based on this, therapies that aim to block or reverse various targets involved in the potential pathogenic mechanisms of neurodegenerative diseases may be promising directions, as current treatment methods that focus on halting a single pathogenic factor have not achieved satisfactory efficacy.

Keywords: Alzheimer’s disease; Huntington’s disease; Lewy body disease; Parkinson’s disease; aging; amyotrophic lateral sclerosis; frontotemporal lobar dementia; genetics; progressive neuron dysfunction and death; protein misfolding.

Figure 1

Timeline showing the potential common pathogenesis of AD, PD, ALS, HD, FTD and LBD as documented in the literature. In this review, we analyzed literature from the past 30 years, spanning from 1997 to 2024. Although the major pathogenesis of NDs remains incompletely understood, researchers have identified numerous important mechanisms over the years, providing crucial clues and evidence for the clinical treatment of NDs. Key findings include the roles of excitotoxicity and mitochondrial dysfunction, which have contributed to the development of Edaravone and Riluzole for ALS treatment. Additionally, the discovery of SOD1 genetic mutations has opened new avenues for gene-modified therapeutics for NDs. Other important factors such as neuroinflammation, the toxic production and aggregation of specific pathogenic proteins, the failure of neural stem cells, and the disruption of gut microbiota homeostasis have also been recognized as contributing to the pathogenesis of NDs, creating new opportunities for novel treatment strategies. AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; FTD: frontotemporal lobar dementia; HD: Huntington’s disease; LBD: Lewy body disease; NDs: neurodegenerative diseases; PD: Parkinson’s disease; SOD1: Cu/Zn superoxide dismutase.

Figure 2

Potential common mechanisms in six neurodegenerative diseases including AD, PD, ALS, HD, FTD, and LBD. Based on current evidence, the potential common mechanisms of NDs may include aging, genetics, progressive neuronal dysfunction and death, protein misfolding and aggregation, propagation of protein aggregates, neuroinflammation, mitochondrial dysfunction, axonal transport defects, and gut microbiota dysbiosis. These mechanisms may interact with one another, collectively contributing to the pathogenesis of NDs. AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; FTD: frontotemporal lobar dementia; HD: Huntington’s disease; LBD: Lewy body disease; NDs: neurodegenerative diseases; PD: Parkinson’s disease; SOD1: Cu/Zn superoxide dismutase.

Figure 3

Common biological processes in the pathogenesis of six neurodegenerative diseases including AD, PD, ALS, HD, FTD, and LBD. These biological processes include aging, genetics, progressive neuronal dysfunction and death, protein misfolding, aggregation and conformational changes, propagation of protein aggregation, neuroinflammation, mitochondrial dysfunction, axonal transport defects, and gut microbiota dysbiosis. Each of these factors may contribute to neurodegeneration through multiple pathways in the pathogenesis of NDs. We propose that these processes interact synergistically to form a pathogenic network that drives neurodegeneration in NDs. AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; FTD: frontotemporal lobar dementia; HD: Huntington’s disease; LBD: Lewy body disease; PD: Parkinson’s disease.