Killing Two Angry Birds with One Stone: Autophagy Activation by Inhibiting Calpains in Neurodegenerative Diseases and Beyond

Weber, Jonasz Jeremiasz; Sena, Priscila Pereira; Singer, Elisabeth; Nguyen, Huu Phuc

doi:10.1155/2019/4741252

Cited by 17 publications

(21 citation statements)

References 172 publications

(200 reference statements)

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“…However, damaging calpain overactivation has been detected in other neurodegenerative disorders, such as Alzheimer disease, amyotrophic lateral sclerosis, Parkinson disease, or the group of polyQ disorders 14 . This calpain overactivation can be caused by an increase of intracellular calcium concentration or by a reduction of the natural endogenous inhibitor calpastatin.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, enhanced calpain activation can contribute to the compromised activation of this degradation pathway. Various studies have found that the impact of calpains on autophagy occurs on multiple levels, such as reduction of autophagy initiation or switching from autophagy to apoptosis 14 . Several neurodegenerative disorders exhibit an overactivation of calpains and disturbances of the autophagic pathway.…”

Section: Discussionmentioning

confidence: 99%

“…In many disease conditions and models calpains were shown to negatively regulate autophagy 14 . In this context, our next objective was to elucidate whether autophagy modulation can affect calpain activity in cultured MNs.…”

Section: Effect Of Calpeptin Treatment On Lc3 Level In Cultured Sma Smentioning

confidence: 99%

“…Knowledge of the molecular and cellular mechanisms of MN degeneration could be extremely relevant to prevention and/or delay of SMA progression and to optimization of recently developed therapies 12,13 . The calpain protease system and autophagy are two major regulatory pathways of the cell that have been correlated to neurodegenerative disorders 14,15 . Calpains are a calcium-dependent family of proteases that participate in calcium-mediated signaling pathways involved in cell processes.…”

Section: Introductionmentioning

confidence: 99%

“…Evidence exists that calpains exert modulatory effects at multiple levels of autophagy 14 . In this context, we recently reported that calpain inhibition increases the SMN protein level in cultured spinal cord MNs and that administration of calpeptin (a well-known calpain inhibitor) to SMA mice models improves lifespan and motor function 21 .…”

Section: Introductionmentioning

confidence: 99%

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Calpain system is altered in survival motor neuron-reduced cells from in vitro and in vivo spinal muscular atrophy models

et al. 2020

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Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by loss of the survival motor neuron 1 (SMN1) gene. SMA is characterized by the degeneration of spinal cord motoneurons (MNs), progressive skeletal muscle atrophy, and weakness. The cellular and molecular mechanisms causing MN loss of function are only partially known. Recent advances in SMA research postulate the role of calpain protease regulating survival motor neuron (SMN) protein and the positive effect on SMA phenotype of treatment with calpain inhibitors. We analyzed the level of calpain pathway members in mice and human cellular SMA models. Results indicate an increase of calpain activity in SMN-reduced MNs. Spinal cord analysis of SMA mice treated with calpeptin, a calpain inhibitor, showed an increase of SMN, calpain, and its endogenous inhibitor calpastatin in MNs. Finally, in vitro calpeptin treatment prevented microtubule-associated protein 1A/1B-light chain 3 (LC3) increase in MNs neurites, indicating that calpain inhibition may reduce autophagosome accumulation in neuron prolongations, but not in soma. Thus, our results show that calpain activity is increased in SMA MNs and its inhibition may have a beneficial effect on SMA phenotype through the increase of SMN in spinal cord MNs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Effect Of Calpeptin Treatment On Lc3 Level In Cultured Sma Smentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Calpain system is altered in survival motor neuron-reduced cells from in vitro and in vivo spinal muscular atrophy models

et al. 2020

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Calpains as novel players in the molecular pathogenesis of spinocerebellar ataxia type 17

Weber

Anger

Sena

et al. 2022

Cell. Mol. Life Sci.

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Spinocerebellar ataxia type 17 (SCA17) is a neurodegenerative disease caused by a polyglutamine-encoding trinucleotide repeat expansion in the gene of transcription factor TATA box-binding protein (TBP). While its underlying pathomechanism is elusive, polyglutamine-expanded TBP fragments of unknown origin mediate the mutant protein’s toxicity. Calcium-dependent calpain proteases are protagonists in neurodegenerative disorders. Here, we demonstrate that calpains cleave TBP, and emerging C-terminal fragments mislocalize to the cytoplasm. SCA17 cell and rat models exhibited calpain overactivation, leading to excessive fragmentation and depletion of neuronal proteins in vivo. Transcriptome analysis of SCA17 cells revealed synaptogenesis and calcium signaling perturbations, indicating the potential cause of elevated calpain activity. Pharmacological or genetic calpain inhibition reduced TBP cleavage and aggregation, consequently improving cell viability. Our work underlines the general significance of calpains and their activating pathways in neurodegenerative disorders and presents these proteases as novel players in the molecular pathogenesis of SCA17.

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NMDA receptor antagonists reduce amyloid-β deposition by modulating calpain-1 signaling and autophagy, rescuing cognitive impairment in 5XFAD mice

Companys-Alemany

Turcu

Schneider

et al. 2022

Cell. Mol. Life Sci.

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Overstimulation of N-methyl-d-aspartate receptors (NMDARs) is the leading cause of brain excitotoxicity and often contributes to neurodegenerative diseases such as Alzheimer’s Disease (AD), the most common form of dementia. This study aimed to evaluate a new NMDA receptor antagonist (UB-ALT-EV) and memantine in 6-month-old female 5XFAD mice that were exposed orally to a chronic low-dose treatment. Behavioral and cognitive tests confirmed better cognitive performance in both treated groups. Calcium-dependent protein calpain-1 reduction was found after UB-ALT-EV treatment but not after memantine. Changes in spectrin breakdown products (SBDP) and the p25/p35 ratio confirmed diminished calpain-1 activity. Amyloid β (Aβ) production and deposition was evaluated in 5XFAD mice and demonstrated a robust effect of NMDAR antagonists on reducing Aβ deposition and the number and size of Thioflavin-S positive plaques. Furthermore, glycogen synthase kinase 3β (GSK3β) active form and phosphorylated tau (AT8) levels were diminished after UB-ALT-EV treatment, revealing tau pathology improvement. Because calpain-1 is involved in autophagy activation, autophagic proteins were studied. Strikingly, results showed changes in the protein levels of unc-51-like kinase (ULK-1), beclin-1, microtubule-associated protein 1A/1B-light chain 3(LC3B-II)/LC3B-I ratio, and lysosomal-associated membrane protein 1 (LAMP-1) after NMDAR antagonist treatments, suggesting an accumulation of autophagolysosomes in 5XFAD mice, reversed by UB-ALT-EV. Likewise, treatment with UB-ALT-EV recovered a WT mice profile in apoptosis markers Bcl-2, Bax, and caspase-3. In conclusion, our results revealed the potential neuroprotective effect of UB-ALT-EV by attenuating NMDA-mediated apoptosis and reducing Aβ deposition and deposition jointly with the autophagy rescue to finally reduce cognitive alterations in a mice model of familial AD.

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Killing Two Angry Birds with One Stone: Autophagy Activation by Inhibiting Calpains in Neurodegenerative Diseases and Beyond

Cited by 17 publications

References 172 publications

Calpain system is altered in survival motor neuron-reduced cells from in vitro and in vivo spinal muscular atrophy models

Calpain system is altered in survival motor neuron-reduced cells from in vitro and in vivo spinal muscular atrophy models

Calpains as novel players in the molecular pathogenesis of spinocerebellar ataxia type 17

NMDA receptor antagonists reduce amyloid-β deposition by modulating calpain-1 signaling and autophagy, rescuing cognitive impairment in 5XFAD mice

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