Calpain-Mediated Signaling Mechanisms in Neuronal Injury and Neurodegeneration

Vosler, Peter S.; Brennan, Christopher S.; Chen, J.

doi:10.1007/s12035-008-8036-x

Cited by 327 publications

(269 citation statements)

References 303 publications

(280 reference statements)

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“…Our data indicate that the depletion of JSAP1 and JLP impaired Ca 2+ homeostasis and increased [Ca 2+ ]i, which in 31 A number of neuronal calpain substrates have been identified, although substrates relevant to neurodegeneration are poorly understood. We used inhibitors to show that JNK and calpain are involved in regulating the axonal degeneration and subsequent neuronal death in Jsap1:Jlp dKO neurons (Figure 7g).…”

Section: Discussionmentioning

confidence: 74%

“…We further investigated whether the Ca 2+ -dependent protease calpain was activated in dKO primary neurons, as calpain is reported to be involved in axonal degeneration and neuronal death. 31 Immunoblotting with an antibody against α-spectrin, a calpain substrate, indicated the presence of proteolytic α-spectrin fragments in cell lysates prepared from (Figure 7e). This α-spectrin cleavage was fully sensitive to MDL28170, a potent inhibitor of calpain 1 and 2, but was not sensitive to SP600125 (Figure 7e).…”

Section: Jsap1 and Jlp Regulate Axonal Transport T Sato Et Almentioning

confidence: 99%

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JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration

et al. 2015

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Axonal transport is critical for neuronal development and function, and defective axonal transport has been implicated in neurodegenerative diseases. However, how axonal transport is regulated, or how defective transport leads to neuronal degeneration, remains unclear. Here, we report that c-Jun NH 2 -terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1, also known as JNK-interacting protein 3 (JIP3)) and JNK-associated leucine zipper protein (JLP) are essential for postnatal brain development. Mice with a double-knockout (dKO) in Jsap1 and Jlp in the dorsal telencephalon developed progressive neuron loss. Using a primary neuron culture system with induced disruption of targeted genes, combined with gene rescue experiments, we show that JSAP1 and JLP regulate kinesin-1-dependent axonal transport with functional redundancy. We also show that the binding of JSAP1 and JLP to kinesin-1 heavy chain is crucial for interactions between kinesin-1 and microtubules. Furthermore, we describe a molecular mechanism by which defective kinesin-1-dependent axonal transport in Jsap1:Jlp dKO neurons causes axonal degeneration and subsequent neuronal death. JNK hyperactivation because of increased intra-axonal Ca 2+ in the Jsap1:Jlp dKO neurons was found to mediate both the axonal degeneration and neuronal death, in cooperation with the Ca 2+ -dependent protease calpain. Our results indicate that axonal JNK may relocate to the nucleus in a dynein-dependent manner, where it activates the transcription factor c-Jun, resulting in neuronal death. Taken together, our data establish JSAP1 and JLP as positive regulators of kinesin-1-dependent axonal transport, which prevents neuronal degeneration.

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Section: Discussionmentioning

confidence: 74%

Section: Jsap1 and Jlp Regulate Axonal Transport T Sato Et Almentioning

confidence: 99%

JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration

et al. 2015

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“…To simplify discussion, only Ca 2þ transients and the resulting local increases of Ca 2þ are cited below as the cause of calpain activation. Note, however, that other calpain regulators, such as phospholipids, protein kinases, calpain-binding proteins, and the ability of some calpains to activate themselves and other calpains through specific cuts, are also involved in controlling calpains, [116][117][118][119][120] thereby shaping the in vivo repertoires of protein fragments generated by these proteases. Figure 1.…”

Section: The Fragment Generation Hypothesismentioning

confidence: 99%

“…Lys-calpain-2 is the Ct fragment of human calpain-2, an activated form of this calpain. [116][117][118][119][120] #34. Asncalpain-B is the calpain-generated Ct fragment of one of two major D. melanogaster calpains and an activated form of this calpain.…”

Section: Protein Fragments Their Generation Despite Deleterious Effementioning

confidence: 99%

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Varshavsky

2012

Protein Science

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Despite extensive understanding of sleep regulation, the molecular-level cause and function of sleep are unknown. I suggest that they originate in individual neurons and stem from increased production of protein fragments during wakefulness. These fragments are transient parts of protein complexes in which the fragments were generated. Neuronal Ca 21 fluxes are higher during wakefulness than during sleep. Subunits of transmembrane channels and other proteins are cleaved by Ca 21 -activated calpains and by other nonprocessive proteases, including caspases and secretases. In the proposed concept, termed the fragment generation (FG) hypothesis, sleep is a state during which the production of fragments is decreased (owing to lower Ca 21 transients) while fragment-destroying pathways are upregulated. These changes facilitate the elimination of fragments and the remodeling of protein complexes in which the fragments resided. The FG hypothesis posits that a proteolytic cleavage, which produces two fragments, can have both deleterious effects and fitness-increasing functions. This (previously not considered) dichotomy can explain both the conservation of cleavage sites in proteins and the evolutionary persistence of sleep, because sleep would counteract deleterious aspects of protein fragments. The FG hypothesis leads to new explanations of sleep phenomena, including a longer sleep after sleep deprivation. Studies in the 1970s showed that ethanol-induced sleep in mice can be strikingly prolonged by intracerebroventricular injections of either Ca 21 alone or Ca 21 and its ionophore (Erickson et al., Science 1978;199:1219-1221 Harris, Pharmacol Biochem Behav 1979;10:527-534; Erickson et al., Pharmacol Biochem Behav 1980;12:651-656). These results, which were never interpreted in connection to protein fragments or the function of sleep, may be accounted for by the FG hypothesis about molecular causation of sleep.

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“…Proteins harboring those mutations include ubiquilin‐1, leading to presenilin aggregation (mutated in some familial AD) (Viswanathan et al ., 2011); ubiquilin‐2 which also targets ubiquitinylated proteins to proteasomes (mutated in ALS) (Zhang et al ., 2014); and parkin, an E3 ubiquitin ligase required for mono‐ubiquitin addition to specific protein targets (mutated in PD) (Roy et al ., 2015). Other predisposing factors can markedly elevate the risk of specific neurological diseases, for example, brain trauma, epilepsy, hypertension, obesity, type 2 diabetes, and exposure to toxic chemicals (in AD, PD) (Vosler et al ., 2008; Zigman, 2013). Age is a major risk factor for almost all neuropathies, as well as an important determinant of disease progression (Brehme et al ., 2014; Fjell et al ., 2014).…”

Section: Introductionmentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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SummaryNeurodegenerative diseases are distinguished by characteristic protein aggregates initiated by disease‐specific ‘seed’ proteins; however, roles of other co‐aggregated proteins remain largely unexplored. Compact hippocampal aggregates were purified from Alzheimer's and control‐subject pools using magnetic‐bead immunoaffinity pulldowns. Their components were fractionated by electrophoretic mobility and analyzed by high‐resolution proteomics. Although total detergent‐insoluble aggregates from Alzheimer's and controls had similar protein content, within the fractions isolated by tau or Aβ1–42 pulldown, the protein constituents of Alzheimer‐derived aggregates were more abundant, diverse, and post‐translationally modified than those from controls. Tau‐ and Aβ‐containing aggregates were distinguished by multiple components, and yet shared >90% of their protein constituents, implying similar accretion mechanisms. Alzheimer‐specific protein enrichment in tau‐containing aggregates was corroborated for individuals by three analyses. Five proteins inferred to co‐aggregate with tau were confirmed by precise in situ methods, including proximity ligation amplification that requires co‐localization within 40 nm. Nematode orthologs of 21 proteins, which showed Alzheimer‐specific enrichment in tau‐containing aggregates, were assessed for aggregation‐promoting roles in C. elegans by RNA‐interference ‘knockdown’. Fifteen knockdowns (71%) rescued paralysis of worms expressing muscle Aβ, and 12 (57%) rescued chemotaxis disrupted by neuronal Aβ expression. Proteins identified in compact human aggregates, bound by antibody to total tau, were thus shown to play causal roles in aggregation based on nematode models triggered by Aβ1–42. These observations imply shared mechanisms driving both types of aggregation, and/or aggregate‐mediated cross‐talk between tau and Aβ. Knowledge of protein components that promote protein accrual in diverse aggregate types implicates common mechanisms and identifies novel targets for drug intervention.

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Calpain-Mediated Signaling Mechanisms in Neuronal Injury and Neurodegeneration

Cited by 327 publications

References 303 publications

JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration

JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

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