Table 1.
Proteotoxicity hallmarks across neurodegenerative diseases.
| Neurodegenerative Disease | Protein Aggregates | IDR Protein Structure | Species Location | Toxicity | References |
|---|---|---|---|---|---|
| Huntington’s disease | Huntingtin | PolyQ | Intracellular (cytosolic and nuclear) | Plasma-membrane integrity disruption Transcriptional dysregulation Reduced levels of neurotrophic factors as BDNF Impairment of protein degradation systems Mitochondrial dysfunction Reactive gliosis Neuroinflammation Cell death |
[4] [5] [6] [7,8] [9,10] [11] [12] [13] |
| Amyotrophic Lateral Sclerosis | TPD-43 | C-Terminal Domain | Cytoplasmic aggregate | Affected mRNA splicing and RNA metabolism proteins Global protein synthesis inhibition Mitochondrial impairment Defective autophagy lysosomal pathway Endocytosis impairment Dysregulated metal ions (as zinc and manganese) Alteration in chromatin dynamics |
[14,15] [16] [17,18] [19,20,21] [22,23] [24,25] [26] |
| FUS | N-Terminal domain | Affected mRNA metabolism and DNA reparation Defects in Protein Quality Control (PQC) system |
[27] [28] |
||
| SOD-1 | 22–30,55–95 region 121–143 region |
Excitotoxity linked to glutamate transporter EAAT2 Excessive calcium influx Mitochondrial dysfunction Compromised axonal transport ROS cytotoxicity RNA species damaged |
[29,30] [29,30] [31,32,33] [34,35,36] [37] [38] |
||
| Ataxin-2 | PolyQ tract | Stress response dysfunction Affected RNA metabolism |
[39] [40] |
||
| TBK-1 | TBK-1 | Autophagy dysfunction | [41] | ||
| Parkinson’s disease | α-Synuclein | C-terminal domain | Intracellular LBs formation, extracellular and membrane | Plasma-membrane integrity disruption Synapse alteration Perturbation in calcium homeostasis Cytoskeleton dynamics altered Protein degradation system dysfunction Lysosomal impact Mitochondrial dysfunction and ROS induction Endoplasmic reticulum stress Golgi transmission affected Modified histone acetylation procedures Apoptosis |
[42,43,44,45] [46,47] [48,49] [50,51,52] [53,54,55] [55,56,57] [58,59] [59,60] [61,62] [63,64,65] [66,67] |
| Alzheimer’s disease | Amyloid-β | Amyloid-β | Extracellular plaques | Plasma-membrane alteration Perturbed synaptic function and structure Glial cells perturbation via mGluR5 receptor Altered calcium homeostasis LTP inhibition in the CA1 region of the hippocampus Oxidative stress disfunction |
[68,69] [70,71,72] [73] [74] [75,76] [77,78] |
| Tau | N-terminal domain | Intracellular neurofibrillary tangles | Telomerase dysfunction Mitochondrial damage and ROS Lipid peroxidation Activated microglia leading to neuronal phagocytosis Apoptosis |
[79,80] [81,82] [83] [84,85] [86] |