| Lineage |
Neuron > Protein Aggregate-Bearing |
| Markers |
Ubiquitin, p62, TDP-43, FUS, SOD1, Alpha-synuclein, Tau |
| Brain Regions |
Motor Cortex, Hippocampus, Substantia Nigra, Spinal Cord, Basal Forebrain |
| Disease Relevance |
Alzheimer's Disease, Parkinson's Disease, ALS, Frontotemporal Dementia, Huntington's Disease |
Protein Aggregate Bearing Neurons plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
Protein aggregate-bearing neurons represent a pathological state characterized by the accumulation of misfolded proteins into insoluble aggregates within the neuronal cytoplasm, nucleus, or processes. These aggregates represent a final common pathway for numerous neurodegenerative diseases, where specific proteins form characteristic inclusions that define the disease nosology [1]. Unlike physiological protein complexes, these aggregates disrupt normal cellular functions through multiple mechanisms including proteostasis disruption, organelle impairment, and toxic gain-of-function effects [2].
The aggregation of proteins is fundamentally a failure of the cellular protein quality control systems, which normally ensure proper folding, timely degradation, and appropriate trafficking of proteins. When these systems become overwhelmed or impaired, aggregation-prone proteins accumulate and form toxic species ranging from soluble oligomers to large insoluble inclusions [3].
- Primary sequence mutations: Amino acid changes promote aggregation [4]
- Post-translational modifications: Phosphorylation, ubiquitination alter solubility [5]
- Oxidative damage: Chemical modifications promote misfolding [6]
- [Stress granule formation: RNA-protein aggregates [7]
- Nucleation-dependent polymerization: Seed formation accelerates aggregation [8]
- Oligomer formation: Toxic soluble intermediate species [9]
- Fibril elongation: Amyloid fibril growth [10]
- Inclusion body formation: Large insoluble aggregates [11]
- Ubiquitin-proteasome system dysfunction: Impaired degradation [12]
- Autophagy-lysosome pathway deficits: Reduced aggregate clearance [13]
- Molecular chaperone impairment: Failed refolding [14]
- ER-associated degradation failure: Misfolded protein accumulation [15]
- Toxic intermediates: More damaging than mature fibrils [16]
- Membrane disruption: Pore-like structures [17]
- Synaptic impairment: Dendritic spine loss [18]
- Propagation capacity: Spread between neurons [19]
- Amyloid structure: Cross-beta sheet conformation [20]
- Stability: Extremely resistant to degradation [21]
- Cell-to-cell transmission: Prion-like propagation [22]
- Strain diversity: Distinct conformational variants [23]
- Lewy bodies: Alpha-synuclein inclusions in PD [24]
- Neurofibrillary tangles: Tau tangles in AD [25]
- Bunina bodies: Tuberous sclerosis protein in ALS [26]
- [Huntington inclusions: Mutant huntingtin aggregates [27]
- Amyloid-beta plaques: Extracellular Aβ deposition [28]
- Neurofibrillary tangles: Hyperphosphorylated tau [29]
- Cerebral amyloid angiopathy: Vascular Aβ deposits [30]
- Neuritic plaques: Surrounded by dystrophic neurites [31]
- Lewy bodies: Intraneuronal alpha-synuclein inclusions [32]
- Lewy neurites: Axonal alpha-synuclein pathology [33]
- Neuromelanin loss: Pigmented neuron degeneration [34]
- Substantia nigra vulnerability: Selective dopaminergic loss [35]
- TDP-43 inclusions: Most common ALS pathology [36]
- SOD1 aggregates: Familial ALS mutations [37]
- FUS inclusions: RNA processing dysfunction [38]
- C9orf72 expansions: Hexanucleotide repeat aggregates [39]
- TDP-43 pathology: Most FTD cases [40]
- Tau pathology: Pick's disease variant [41]
- FUS inclusions: Rare FTD subtypes [42]
- Progranulin mutations: Lysosomal dysfunction [43]
- Mutant huntingtin aggregates: Polyglutamine expansions [44]
- Nuclear inclusions: Transcriptional dysregulation [45]
- Neuronal intranuclear inclusions: Inclusions in neurons [46]
- Axonal transport impairment: Huntingtin dysfunction [47]
- Proteasome inhibition: Aggregates impair function [48]
- Chaperone sequestration: Hsp70/90 recruited to aggregates [49]
- Translation impairment: Ribosome stalling on aggregates [50]
- ER stress: Accumulated misfolded proteins [51]
- Mitochondrial dysfunction: Energy deficit [52]
- Lysosomal damage: Leakage of cathepsins [53]
- Golgi fragmentation: Protein processing disruption [54]
- Nuclear envelope disruption: Import/export problems [55]
- ER calcium leak: Dysregulated calcium [56]
- Synaptic vesicle impairment: Neurotransmitter release defects [57]
- Axonal transport blockade: Organelle trafficking disruption [58]
- Membrane protein mislocalization: Receptor dysfunction [59]
- Immunotherapy: Antibody-based approaches [60]
- Small molecule inhibitors: Prevent aggregation [61]
- Gene silencing: siRNA/antisense oligonucleotides [62]
- [Autophagy induction: Enhance clearance [63]
- Proteasome activation: Enhance degradation [64]
- Chaperone upregulation: Heat shock protein induction [65]
- Autophagy enhancement: mTOR inhibition [66]
- [ER stress modulation: UPR enhancement [67]
- Antioxidants: Reduce oxidative stress [68]
- Anti-apoptotic drugs: Prevent cell death [69]
- Metabolic support: Enhance energy production [70]
- Anti-inflammatory agents: Reduce neuroinflammation [71]
- Protein expression systems: Recombinant protein aggregation [72]
- Cell culture models: Transient transfection [73]
- [iPSC-derived neurons: Patient-specific aggregates [74]
- Organoid systems: 3D aggregation models [75]
- Transgenic models: Disease-causing mutations [76]
- Viral vector models: Aggregate induction [77]
- Knock-in models: Human mutations in mice [78]
- [C. elegans models: Simple aggregation [79]
Protein Aggregate Bearing Neurons plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
The study of Protein Aggregate Bearing Neurons has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Ross, C.A. & Poirier, M.A. (2004). Protein aggregation and neurodegenerative disease. Nature Medicine
- Soto, C. & Estrada, L.D. (2008). Protein misfolding and neurodegeneration. Archives of Neurology
- Taylor, J.P. et al. (2002). Protein aggregation in neurodegeneration. Nature Reviews Neuroscience
- Chiti, F. & Dobson, C.M. (2006). Protein misfolding, functional amyloid, and human disease. Annual Review of Biochemistry
- Tenreiro, S. et al. (2014). Phosphorylation in alpha-synuclein aggregation. Journal of Neurochemistry
- Butterfield, D.A. & Kanski, J. (2001). Protein oxidation in aging and neurodegenerative disease. Brain Research Reviews
- Wolozin, B. (2012). Regulated protein aggregation. Prion
- Harper, J.D. & Lansbury, P.T. (1997). Models of amyloid seeding. Annual Review of Biochemistry
- Glabe, C.G. (2006). Common mechanisms of amyloid oligomer pathogenesis in degenerative disease. Aging Cell
- Sunde, M. & Blake, C. (1997). The structure of amyloid fibrils. Quarterly Reviews of Biophysics
- Goedert, M. et al. (2010). Amyloid deposits in neurodegenerative diseases. Nature Reviews Neuroscience
- Ciechanover, A. (2005). Proteasome function: from Nobel prizes to new biology. Molecular Cell
- Nixon, R.A. (2007). Autophagy in neuronal health and disease. New England Journal of Medicine
- Hartl, F.U. & Hayer-Hartl, M. (2009). Molecular chaperones in protein folding. Science
- Hampton, R.Y. (2002). ER-associated degradation in protein quality control and disease. Current Opinion in Cell Biology
- Walsh, D.M. & Selkoe, D.J. (2007). A beta oligomers: a decade of discovery. Journal of Neuroscience
- Kayed, R. et al. (2003). Common structure of soluble amyloid oligomers. Science
- Shankar, G.M. et al. (2008). Amyloid-beta protein dimers. Journal of Neuroscience
- Jucker, M. & Walker, L.C. (2011). Pathogenic protein seeding in Alzheimer disease. Annals of Neurology
- Fändrich, M. (2007). On the structural definition of amyloid fibrils. Biophysical Chemistry
- Swan, C.E. & Breydo, L. (2013). Mechanism of amyloid fibril formation. FEBS Letters
- Prusiner, S.B. (2012). A unifying role for prions in neurodegenerative diseases. Science
- Peterson, D. et al. (2008). Amyloid strains. Journal of Molecular Biology
- Spillantini, M.G. & Goedert, M. (2013). The alpha-synucleinopathies. Handbook of Clinical Neurology
- Ballatore, C. et al. (2007). Tau-mediated neurodegeneration in Alzheimer's disease. Nature Reviews Neuroscience
- Bunina, T.T. (1962). Intracellular proteinaceous inclusions. Zhurnal Nevropatologii i Psikhiatrii Imeni S.S. Korsakova
- Davies, S.W. et al. (1997). Formation of neuronal intranuclear inclusions. Cell
- Hardy, J. & Selkoe, D.J. (2002). The amyloid hypothesis of Alzheimer's disease. Science
- Grundke-Iqbal, I. et al. (1986). Abnormal phosphorylation of the microtubule-associated protein tau. Proceedings of the National Academy of Sciences
- Weller, R.O. et al. (2008). Cerebral amyloid angiopathy. Nature Reviews Neurology
- Terry, R.D. et al. (1964). Neuritic plaques and neurofibrillary tangles. Journal of Neuropathology & Experimental Neurology
- Lewy, F.H. (1912). Paralysis agitans. Pathologische Anatomie
- Braak, H. et al. (1999). Staging of brain pathology related to sporadic Parkinson's disease. Neurobiology of Aging
- Zecca, L. et al. (2004). Neuromelanin in the human brain. Brain Research Reviews
- Forno, L.S. (1996). Neuropathology of Parkinson's disease. Journal of Neuropathology & Experimental Neurology
- Neumann, M. et al. (2006). Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science
- Rosen, D.R. et al. (1993). Mutations in Cu/Zn superoxide dismutase gene. Nature
- Kwiatkowski, T.J. et al. (2009). Mutations in the FUS/TLS gene on chromosome 16. Nature Genetics
- DeJesus-Hernandez, M. et al. (2011). Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 gene. Neuron
- Mackenzie, I.R. et al. (2010). Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration. Journal of Neuropathology & Experimental Neurology
- Pick, A. (1892). Uber einen weiteren Fall von chronischer progressiver Hirnatrophie. Wiener medizinische Wochenschrift
- Urwin, H. et al. (2010). FUS pathology in basophilic inclusion body disease. Acta Neuropathologica
- Baker, M. et al. (2006). Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature
- The Huntington's Disease Collaborative Research Project. (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell
- Nucifora, F.C. et al. (2001). Interference by huntingtin and atrophin-1 with CBP-mediated transcription. Science
- DiFiglia, M. et al. (1997). Huntingtin-positive neurons in Huntington disease. Science
- Gunawardena, S. et al. (2003). Disruption of axonal transport by loss of huntingtin. Journal of Cell Biology
- Bence, N.F. et al. (2001). Impairment of the ubiquitin-proteasome system by protein aggregation. Science
- Prapre, K. & Frydman, J. (2006). The Hsp70 family. Current Opinion in Structural Biology
- Liu-Yesucevitz, L. et al. (2010). ALS-associated mutations in TDP-43 affect stress granule formation. Journal of Neuroscience
- Kaufman, R.J. (1999). Stress signaling from the lumen of the endoplasmic reticulum. Genes & Development
- Lin, M.T. & Beal, M.F. (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature
- Alvarez-Erviti, L. et al. (2011). Lysosomal dysfunction and autophagy impairment in Parkinson's disease. Autophagy
- Gonatas, N.K. et al. (2006). Fragmentation of the Golgi apparatus in neurodegenerative diseases. Brain Research Reviews
- Marmiroli, S. &映射, A. (2012). Nuclear envelope dysfunction. Nature Reviews Neurology
- Duchen, M.R. (2004). Mitochondria and calcium. Cell Calcium
- Miller, L.C. & Cantrell, A. (2006). Synaptic vesicle proteins in neurodegenerative disease. Neurochemical Research
- Morfini, G.A. et al. (2009). Axonal transport defects in neurodegenerative diseases. Journal of Neuroscience
- Tien, N.W. & Feller, M.B. (2011). Membrane protein mislocalization in neurodegenerative disease. Nature Reviews Neuroscience
- Levin, E.C. et al. (2009). Immunotherapy for Alzheimer's disease. Current Alzheimer Research
- Eisele, Y.S. et al. (2015). Targeting protein aggregation for the treatment of neurodegenerative diseases. Nature Reviews Drug Discovery
- Foust, K.D. et al. (2013). Therapeutic AAV9-mediated suppression of mutant SOD1. Molecular Therapy
- Sarkar, S. & Rubinsztein, D.C. (2008). Huntington's disease: degradation of mutant huntingtin by autophagy. The FEBS Journal
- Schmidt, M. & Finley, D. (2014). Dynamics of the proteasome system. Annual Review of Biochemistry
- Sreedharan, J. & Brown, R.H. (2013). Amyotrophic lateral sclerosis: problems and prospects. Annals of Neurology
- Rubinsztein, D.C. et al. (2015). Autophagy and neurodegeneration. Nature
- Wang, M. & Kaufman, R.J. (2016). Protein misfolding in the endoplasmic reticulum. Nature Reviews Disease Primers
- Sayre, L.M. et al. (2008). Oxidative stress in neurodegeneration. Free Radical Biology and Medicine
- O'Brien, R.J. & Wong, P.C. (2011). Amyloid precursor protein processing and Alzheimer's disease. Annual Review of Neuroscience
- Cunnane, S. et al. (2011). Brain fuel metabolism and Alzheimer's disease. Nutrition
- Heneka, M.T. et al. (2015). Neuroinflammation in Alzheimer's disease. Lancet Neurology
- Serpell, L.C. (2000). Alzheimer's amyloid fibrils. Journal of Molecular Biology
- Li, J. et al. (2008). ALS-associated SOD1 mutant G85R forms aggregates. Journal of Biological Chemistry
- Kondo, T. et al. (2013). iPSC models of Alzheimer's disease. Cell Stem Cell
- Choi, S.H. et al. (2014). Three-dimensional brain-like tissue model. Nature
- Jankord, R. & Herman, J.P. (2008). Limbic regulation of HPA axis. Stress
- Lee, M.K. et al. (2002). Expression of human mutant SOD1 in motor neurons. Neurobiology of Disease
- Menalled, L.B. (2005). Knock-in mouse models of Huntington's disease. NeuroRx
- Teschendorf, D. & Link, C.D. (2009). C. elegans models of neurodegenerative disease. Neuromolecular Medicine