CTSB (Cathepsin B) encodes cathepsin B, a lysosomal cysteine protease belonging to the papain family. Cathepsin B is one of the most studied cathepsins due to its involvement in protein degradation, antigen processing, and more importantly, in the pathogenesis of [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and other neurodegenerative disorders. Its dual endopeptidase and exopeptidase (carboxypeptidase) activities make it unique among cathepsins. [@hook2008]
CTSB (Cathepsin B) encodes cathepsin B, a lysosomal cysteine protease belonging to the papain family. Cathepsin B is one of the most studied cathepsins due to its involvement in protein degradation, antigen processing, and more importantly, in the pathogenesis of [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and other neurodegenerative disorders. Its dual endopeptidase and exopeptidase (carboxypeptidase) activities make it unique among cathepsins. [@hook2008]
Gene Information
Gene Symbol: CTSB
Official Name: Cathepsin B
Chromosomal Location: 8p23.1
NCBI Gene ID: 1508
Uniprot ID: P07846
Protein Structure and Function
Cathepsin B is synthesized as a preproenzyme and undergoes processing: [@benes2008]
Processing and Activation
Preprocathepsin B: N-terminal signal peptide directs to ER
Procathepsin B: Signal peptide cleaved in ER, forms inactive zymogen
Active cathepsin B: Cleaved in acidic lysosomes to form active enzyme
Structural Features
Molecular weight: ~26 kDa (mature form)
Active site: Cys29, His159, Asn175 (catalytic triad)
[Oligodendrocytes](/cell-types/oligodendrocytes) Cellular localization: Primarily lysosomal, but can be secreted
Role in Neurodegenerative Diseases
Alzheimer's Disease
Cathepsin B plays multiple roles in AD pathogenesis [1][2]: [@zhang2009]
Amyloid-beta Metabolism
Aβ generation: Cathepsin B can cleave [amyloid precursor protein](/entities/app-protein) (APP) at β- and [γ-secretase](/entities/gamma-secretase) sites, potentially generating Aβ peptides [3]
Aβ degradation: Paradoxically, cathepsin B can also degrade [Aβ42](/proteins/amyloid-beta), reducing aggregation [4]
AChE interaction: Cathepsin B may work with acetylcholinesterase to enhance Aβ aggregation [5]
Neuroinflammation
Pro-inflammatory signaling: Cathepsin B activates [NLRP3 inflammasome](/entities/nlrp3-inflammasome) in microglia [6]
IL-1β processing: Converts pro-IL-1β to active IL-1β
TNF-α processing: Generates active TNF-α
Tau Pathology
Tau cleavage: Cathepsin B can cleave [tau protein](/proteins/tau), generating toxic fragments [7]
Lysosomal dysfunction: Impairs [autophagy](/entities/autophagy), affecting tau clearance
Parkinson's Disease
Cathepsin B is implicated in PD through multiple mechanisms [8]: [@muellersteiner2006]
α-Synuclein Processing
Degradation: Can degrade [α-synuclein](/proteins/alpha-synuclein) aggregates [9]
Generation of toxic fragments: Cleavage may generate aggregation-prone fragments
Secretion: May promote cell-to-cell spread of α-synuclein pathology
Dopaminergic Neuron Vulnerability
Mitochondrial dysfunction: Cathepsin B release from damaged lysosomes triggers [apoptosis](/entities/apoptosis) [10]
oxidative stress: Enhanced cathepsin B activity in PD brains
LRRK2 Interaction
[LRRK2](/entities/lrrk2) mutations affect lysosomal function and cathepsin B activity [11]
Amyotrophic Lateral Sclerosis
[TDP-43](/mechanisms/tdp-43-proteinopathy) pathology: Cathepsin B may process TDP-43 fragments [12]
Motor neuron degeneration: Lysosomal leakage and cathepsin B release
Astrocyte reactivity: Increased cathepsin B in ALS astrocytes
Other Neurodegenerative Disorders
Huntington's Disease
Mutant [huntingtin](/proteins/huntingtin) affects lysosomal function, altering cathepsin B activity [13]
May contribute to striatal neuron death
Multiple Sclerosis
Demyelination involves cathepsin B-mediated myelin protein degradation [14]
Microglial cathepsin B in lesion formation
Therapeutic Implications
Cathepsin B as Drug Target
Inhibitors
CA-074: Selective cathepsin B inhibitor
E-64: Broad cysteine protease inhibitor
Novel brain-penetrant inhibitors: Being developed for neurodegenerative diseases
Challenges
Peripheral vs. central effects: Inhibitors must cross the [blood-brain barrier](/entities/blood-brain-barrier)
Compensatory mechanisms: Other cathepsins may compensate
Physiological functions: Complete inhibition may cause side effects
Protective vs. Harmful Effects
The role of cathepsin B in neurodegeneration is complex: [@cai2011]
Harmful: Inflammasome activation, Aβ generation, tau cleavage
Protective: Aβ degradation, α-synuclein clearance
This dual role complicates therapeutic targeting. [@hornung2008]
Biochemical Pathways
Lysosomal Degradation
Protein substrates → Endocytosis → Lysosome → Cathepsin B cleavage → Amino acids