Involvement of calpain in AMPA-induced toxicity to rat cerebellar Purkinje neurons

Mansouri, Bobbak; Henne, W.; Oomman, Sowmini; Bliss, Richard; Attridge, Jennifer; Finckbone, VelvetLee; Zeitouni, Tarek; Hoffman, Trent; Bahr, Ben A.; Strahlendorf, Howard K.; Strahlendorf, Jean C.

doi:10.1016/j.ejphar.2006.11.032

Cited by 18 publications

(15 citation statements)

References 39 publications

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“…DCD in this model represents approximately 20% to 30% of PCs at 8 months, as already reported (16). This phenomenon is caused by an increase in [Ca 2+ ] cyto , thus activating calpains, which are Ca 2+ -sensitive cysteine proteases that mediate cytoskeletal breakdown (30)(31)(32). Looking for molecular evidence of activation of this pathway in SCA28, we assayed calpainmediated proteolysis of αII-spectrin, which was expected to result in 2 proteolytic fragments of nearly equal electrophoretic mobility (~150 kDa) (33).…”

Section: Introductionmentioning

confidence: 68%

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Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model

Maltecca¹,

Baseggio²,

Consolato³

et al. 2014

J. Clin. Invest.

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Spinocerebellar ataxia type 28 (SCA28) is a neurodegenerative disease caused by mutations of the mitochondrial protease AFG3L2. The SCA28 mouse model, which is haploinsufficient for Afg3l2, exhibits a progressive decline in motor function and displays dark degeneration of Purkinje cells (PC-DCD) of mitochondrial origin. Here, we determined that mitochondria in cultured Afg3l2-deficient PCs ineffectively buffer evoked Ca2+ peaks, resulting in enhanced cytoplasmic Ca2+ concentrations, which subsequently triggers PC-DCD. This Ca2+-handling defect is the result of negative synergism between mitochondrial depolarization and altered organelle trafficking to PC dendrites in Afg3l2-mutant cells. In SCA28 mice, partial genetic silencing of the metabotropic glutamate receptor mGluR1 decreased Ca2+ influx in PCs and reversed the ataxic phenotype. Moreover, administration of the β-lactam antibiotic ceftriaxone, which promotes synaptic glutamate clearance, thereby reducing Ca2+ influx, improved ataxia-associated phenotypes in SCA28 mice when given either prior to or after symptom onset. Together, the results of this study indicate that ineffective mitochondrial Ca2+ handling in PCs underlies SCA28 pathogenesis and suggest that strategies that lower glutamate stimulation of PCs should be further explored as a potential treatment for SCA28 patients

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Section: Introductionmentioning

confidence: 68%

“…Organotypic slices from cerebellum were prepared from P10 mice, as previously described (32). Cerebella were removed from newborn Afg3l2 mice.…”

Section: Discussionmentioning

confidence: 99%

Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model

Maltecca¹,

Baseggio²,

Consolato³

et al. 2014

J. Clin. Invest.

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“…Excessive neurotransmitter activity activates calcium-dependent proteases. In the nervous system, αII spectrin is a major target of calpain; its cleavage is a sensitive measure of neuronal remodeling or neurodegeneration or neurotoxicity and is an early event in the generation of dark Purkinje cells (34). In normal littermates, no αII spectrin BDPs can be detected by either Western blot or immunohistology (Fig.…”

Section: Resultsmentioning

confidence: 99%

Targeted deletion of βIII spectrin impairs synaptogenesis and generates ataxic and seizure phenotypes

Stankewich¹,

Gwynn

Ardito³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The spectrin membrane skeleton controls the disposition of selected membrane channels, receptors, and transporters. In the brain βIII spectrin binds directly to the excitatory amino acid transporter (EAAT4), the glutamate receptor delta, and other proteins. Mutations in βIII spectrin link strongly to human spinocerebellar ataxia type 5 (SCA5), correlating with alterations in EAAT4. We have explored the mechanistic basis of this phenotype by targeted gene disruption of Spnb3. Mice lacking intact βIII spectrin develop normally. By 6 months they display a mild nonprogressive ataxia. By 1 year most Spnb3 −/− animals develop a myoclonic seizure disorder with significant reductions of EAAT4, EAAT1, GluRδ, IP3R, and NCAM140. Other synaptic proteins are normal. The cerebellum displays increased dark Purkinje cells (PC), a thin molecular layer, fewer synapses, a loss of dendritic spines, and a 2-fold expansion of the PC dendrite diameter. Membrane and expanded Golgi profiles fill the PC dendrite and soma, and both regions accumulate EAAT4. Correlating with the seizure disorder are enhanced hippocampal levels of neuropeptide Y and EAAT3 and increased calpain proteolysis of αII spectrin. It appears that βIII spectrin disruption impairs synaptogenesis by disturbing the intracellular pathways selectively regulating protein trafficking to the synapse. The mislocalization of these proteins secondarily disrupts glutamate transport dynamics, leading to seizures, neuronal damage, and compensatory changes in EAAT3 and neuropeptide Y.cytoskeleton | membrane | spinocerebellar ataxia type 5 | excitatory amino acid transporter 4 | Purkinje T he mammalian nervous system expresses seven spectrin genes, two encoding α-subunits and five encoding β-subunits. All are large multifunctional molecules, and all display distinctive cellular and subcellular distributions. Their role in neuronal cells remains largely conjectural. Although generally thought to organize the membrane surface or to bestow membrane stability, their diversity implies a function beyond simple stabilization. Studies in cultured cells reveal spectrin and ankyrin as scaffolds organizing internal organelles (1-6) or receptor clusters (7-10). These proteins also facilitate protein transport in the secretory (3, 10, 11) and endocytic pathways (12-14) (reviewed in ref. 15). Consonant with these roles are observations that genetic deletion or mutation of spectrins or ankyrins may cause missorting of unique subsets of adhesion molecules, receptors, and ion channels in brain or muscle, with consequential cardiovascular, neuromuscular, and neurodegenerative disease (16-18).In the nervous system, cortical (19) and cerebellar granular cell neurons (7) are enriched in βI spectrin, especially at the postsynaptic density (PSD) and on a subset of vesicular organelles. Spectrin βII is associated with axonal processes (20), and βIV spectrin is concentrated at the nodes of Ranvier and along the initial axon segment (21). Less is known about βIII spectrin, although studies point to an intere...

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“…Accordingly, Afg3l2 haploinsufficient mice recapitulate most features of SCA28 patients, displaying defects in motor coordination and balance due to dark degeneration of Purkinje cells (PC-DCD) (14). The latter is a phenomenon documented in other SCAs as secondary to excitotoxicity and high levels of intracellular Ca 2+ , which cause calpain-mediated cytoskeletal breakdown (15,16). Peculiarly, in the SCA28 model, PC-DCD originates from mitochondrial dysfunction, as demonstrated by the fact that alterations in mitochondrial morphology and metabolism precede PC degeneration (14).…”

Section: Introductionmentioning

confidence: 99%

Respiratory dysfunction by AFG3L2 deficiency causes decreased mitochondrial calcium uptake via organellar network fragmentation

Maltecca

Stefani

Cassina

et al. 2012

Human Molecular Genetics

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The mitochondrial protein AFG3L2 forms homo-oligomeric and hetero-oligomeric complexes with paraplegin in the inner mitochondrial membrane, named m-AAA proteases. These complexes are in charge of quality control of misfolded proteins and participate in the regulation of OPA1 proteolytic cleavage, required for mitochondrial fusion. Mutations in AFG3L2 cause spinocerebellar ataxia type 28 and a complex neurodegenerative syndrome of childhood. In this study, we demonstrated that the loss of AFG3L2 in mouse embryonic fibroblasts (MEFs) reduces mitochondrial Ca2+ uptake capacity. This defect is neither a consequence of global alteration in cellular Ca2+ homeostasis nor of the reduced driving force for Ca2+ internalization within mitochondria, since cytosolic Ca2+ transients and mitochondrial membrane potential remain unaffected. Moreover, experiments in permeabilized cells revealed unaltered mitochondrial Ca2+ uptake speed in Afg3l2−/− cells, indicating the presence of functional Ca2+ uptake machinery. Our results show that the defective Ca2+ handling in Afg3l2−/− cells is caused by fragmentation of the mitochondrial network, secondary to respiratory dysfunction and the consequent processing of OPA1. This leaves a number of mitochondria devoid of connections to the ER and thus without Ca2+ elevations, hampering the proper Ca2+ diffusion along the mitochondrial network. The recovery of mitochondrial fragmentation in Afg3l2−/− MEFs by overexpression of OPA1 rescues the impaired mitochondrial Ca2+ buffering, but fails to restore respiration. By linking mitochondrial morphology and Ca2+ homeostasis, these findings shed new light in the molecular mechanisms underlining neurodegeneration caused by AFG3L2 mutations.

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Involvement of calpain in AMPA-induced toxicity to rat cerebellar Purkinje neurons

Cited by 18 publications

References 39 publications

Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model

Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model

Targeted deletion of βIII spectrin impairs synaptogenesis and generates ataxic and seizure phenotypes

Respiratory dysfunction by AFG3L2 deficiency causes decreased mitochondrial calcium uptake via organellar network fragmentation

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