S-Nitrosylation of cathepsin B affects autophagic flux and accumulation of protein aggregates in neurodegenerative disorders

Challenges in Batch-to-Bed Translation Involving Inflammation-Targeting Compounds in Chronic Epilepsy: The Case of Cathepsin Activity-Based Probes

“…30 However, inhibition of the same cathepsin was also associated with increased neurodegeneration, contributing to Alzheimer's disease pathology. 31 These reports imply an important role for lysosomal cathepsin B in the degradation of pathologic proteins, suggesting the need for complex and careful regulation of its activity in various cellular and extracellular compartments rather than favoring its complete inhibition.…”

Aberrant protein S-nitrosylation contributes to hyperexcitability-induced synaptic damage in Alzheimer’s disease: Mechanistic insights and potential therapies

“…Here, we review the involvement of redox-mediated posttranslational modifications such as protein S-nitrosylation, in part triggered by excessive glutamate receptor activity, causing additional changes in glutamate receptors and other deleterious pathways. Other pathways disrupted by aberrant protein S-nitrosylation, but beyond the scope of the current review, include autophagy, which would otherwise clear misfolded/aggregated proteins, other protein folding machinery, chaperone activity, metabolism needed for synaptic maintenance, and many other cellular processes ( Uehara et al, 2006 ; Nakamura et al, 2013 , 2021c ; Nakamura and Lipton, 2017 ; Kim et al, 2022 ; Oh et al, 2022a ). Taken together, these events result in hyperexcitability contributing to synaptic damage.…”

Cathepsin B in programmed cell death machinery: mechanisms of execution and regulatory pathways

“…In addition to CatB-mediated autophagy in infection model, it was also reported that increased S-nitrosylation of CatB in both AD mouse and flash-frozen postmortem human AD brains. This posttranslational modification of CatB inhibits its enzymatic activity, blocks autophagic flux, and leads to accumulation of protein aggregates that finally contributes to Alzheimer’s disease pathogenesis [ 40 ]. It is worth noting that CatB may involve in autophagy-associated cell death, but lacking evidence of its involvement in autophagy-dependent cell death.…”

“… [ 63 , 112 ] Parkinson’s disease (PD) MPTP-induced PD model mice; A53T α-Syn treated BV2 cell 2–4 – Microglia、dopamine neuron α-Syn activates NLRP3 inflammasomes through microglial endocytosis and subsequent lysosomal CatB release then inducing cell death [ 57 ] Alzheimer’s disease (AD) 5xFAD transgenic mouse – down Cerebrocortical primary cell cultures S-nitrosylating the lysosomal protease CatB inhibits CatB activity and then induces caspase-dependent neuronal apoptosis. [ 40 ] Alzheimer’s disease Aβ-treated BV2 cell; peptide chromogranin A treated primary microglia; human amyloid precursor protein (hAPP) model mouse 2–4 up Microglia; Primary cortical neurons Aβ/chromogranin-treated microglia causes the release of CatB into the cytoplasm, causing microglia apoptosis, and CatB is released outside the cell, causing neuronal death. [ 59 , 100 , 113 ] Retinitis pigmentosa rd10 mouse carried a missense mutation in the Pde6b gene – Decreased in lysosomes and increased in the cytoplasm Photoreceptor cells CatB translocates to the cytosol and then promotes apoptosis.…”

“…The cytoplasmic CatB expression has been found to be upregulated in postmortem brain tissue of patients with various neurological diseases, including cerebral ischemia, traumatic brain injury (TBI), and neurodegenerative diseases [40,[55][56][57]. CatB is sequestered primarily in the lysosomes and vesicles of the regulated secretory pathway, and is rarely found in the cytosol of healthy cells.…”