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Huntington's disease (HD) is caused by polyglutamine expansion (exp) in huntingtin. Here, we used a yeast artificial chromosome (YAC) transgenic mouse model of HD to investigate the connection between disturbed calcium ([Ca.sup.2+]) signaling and apoptosis of HD medium spiny neurons (MSN). Repetitive application of glutamate elevates cytosolic [Ca.sup.2+] levels in MSN from the YAC128 mouse but not in MSN from the wild-type or control YAC18 mouse. Application of glutamate results in apoptosis of YAC128 MSN but not wild-type or YAC18 MSN. Analysis of glutamate-induced apoptosis of the YAC128 MSN revealed that (i) actions of glutamate are mediated by mGluR1/5 and NR2B glutamate receptors; (ii) membrane-permeable inositol 1,4,5-trisphosphate receptor blockers 2-APB and Enoxaparin (Lovenox) are neuroprotective; (iii) apoptosis involves the intrinsic pathway mediated by release of mitochondrial cytochrome c and activation of caspases 9 and 3; (iv) apoptosis requires mitochondrial [Ca.sup.2+] overload and can be prevented by the mitochondrial [Ca.sup.2+] uniporter blocker Ruthenium 360; and (v) apoptosis involves opening of mitochondrial permeability transition pore (MPTP) and can be prevented by MPTP blockers such as bongkrekic acid, Nortriptyline, Desipramine, Trifluoperazine, and Maprotiline. These findings describe a pathway directly linking disturbed [Ca.sup.2+] signaling and degeneration of MSN in the caudate nucleus in HD. These findings also suggest that [Ca.sup.2+] and MPTP blockers may have a therapeutic potential for treatment of HD. Enoxaparin | neurodegeneration | transgenic mouse | mitochondria | Lovenox

Minocycline is broadly protective in neurologic disease models featuring cell death and is being evaluated in clinical trials. We previously demonstrated that minocycline-mediated protection against caspase-dependent cell death related to its ability to prevent mitochondrial cytochrome c release. These results do not explain whether or how minocycline protects against caspase-independent cell death. Furthermore, there is no information on whether Smac/Diablo or apoptosis-inducing factor might play a role in chronic neurodegeneration. In a striatal cell model of Huntington's disease and in R6/2 mice, we demonstrate the association of cell death/disease progression with the recruitment of mitochondrial caspase-independent (apoptosis-inducing factor) and caspase-dependent (Smac/Diablo and cytochrome c) triggers. We show that minocycline is a drug that directly inhibits both caspase-independent and -dependent mitochondrial cell death pathways. Furthermore, this report demonstrates recruitment of Smac/Diablo and apoptosis-inducing factor in chronic neurodegeneration. Our results further delineate the mechanism by which minocycline mediates its remarkably broad neuroprotective effects.

Three biologically cloned isolates of feline leukemia viruses (FeLV)-C were studied to determine whether anemogenic subgroup C FeLV share common genetic determinants. Results show that the only consistent features distinguishing deduced FeLV-A and FeLV-C proteins were the lysine-to-arginine change and structural prediction of an alpha helix in FeLV-A proteins against random coil in FeLV-C proteins within V1.

Neuritic retraction in the absence of overt neuronal death is a shared feature of normal aging and neurodegenerative disorders, but the intracellular mechanisms modulating this process are not understood. We propose that cumulative distal mitochondrial protein damage results in impaired protein import, leading to mitochondrial dysfunction and focal activation of the canonical apoptosis pathway in neurites. This is a controlled process that may not lead to neuronal death and, thus, we term this phenomenon "neuritosis." Consistent with our hypothesis, we show that in primary cerebrocortical neurons, mitochondrial distance from the soma correlates with increased mitochondrial protein damage, PINK1 accumulation, reactive oxygen species production, and decreased mitochondrial membrane potential and depolarization threshold. Furthermore, we demonstrate that the distance-dependent mitochondrial membrane potential gradient exists in vivo in mice. We demonstrate that impaired distal mitochondria have a lower threshold for focal/nonlethal neuritic caspase-3 activation in normal neurons that is exacerbated in aging, stress, and neurodegenerative conditions, thus delineating a fundamental mechanistic underpinning for synaptic vulnerability. [ABSTRACT FROM AUTHOR]

Brown adipose tissue (BAT) mitochondria exhibit high oxidative capacity and abundant expression of both electron transport chain components and uncoupling protein 1 (UCP1). UCP1 dissipates the mitochondrial proton motive force (Δp) generated by the respiratory chain and increases thermogenesis. Here we find that in mice genetically lacking UCP1, cold-induced activation of metabolism triggers innate immune signaling and markers of cell death in BAT. Moreover, global proteomic analysis reveals that this cascade induced by UCP1 deletion is associated with a dramatic reduction in electron transport chain abundance. UCP1-deficient BAT mitochondria exhibit reduced mitochondrial calcium buffering capacity and are highly sensitive to mitochondrial permeability transition induced by reactive oxygen species (ROS) and calcium overload. This dysfunction depends on ROS production by reverse electron transport through mitochondrial complex I, and can be rescued by inhibition of electron transfer through complex I or pharmacologic depletion of ROS levels. Our findings indicate that the interscapular BAT of Ucp1 knockout mice exhibits mitochondrial disruptions that extend well beyond the deletion of UCP1 itself. This finding should be carefully considered when using this mouse model to examine the role of UCP1 in physiology. [ABSTRACT FROM AUTHOR]

Huntington's disease (HO) is caused by polyglutamine expansion (exp) in huntingtin. Here, we used a yeast artificial chromosome (YAC) transgenic mouse model of HD to investigate the connection between disturbed calcium (Ca2+ signaling and apoptosis of HD medium spiny neurons (MSN). Repetitive application of glutamate elevates cytosolic Ca2+ levels in MSN from the YAC128 mouse but not in MSN from the wild-type or control YAC18 mouse. Application of glutamate results in apoptosis of YAC128 MSN but not wild-type or YAC18 MSN. Analysis of glutamate-induced apoptosis of the YAC128 MSN revealed that (i) actions of glutamate are mediated by mGluR1/S and NRZB glutamate receptors; (10 membrane-permeable inositol 1,4,5-trisphosphate receptor blockers 2-APB and Enoxaparin (Lovenox) are neuroprotective; (110 apoptosis involves the intrinsic pathway mediated by release of mitochondrial cytochrome c and activation of caspases 9 and 3; (iv) apoptosis requires mitochondrial Ca2+ overload and can be prevented by the mitochondrial Ca2+ uniporter blocker Ruthenium 360; and (v) apoptosis involves opening of mitochondrial permeability transition pore (MPTP) and can be prevented by MPTP blockers such as bongkrekic acid, Nortriptyline, Desipramine, Influoperazine, and Maprotiline. These findings describe a pathway directly linking disturbed Ca2+ signaling and degeneration of MSN in the caudate nucleus in HD. These findings also suggest that Ca2+ and MPTP blockers may have a therapeutic potential for treatment of HD. [ABSTRACT FROM AUTHOR]

Minocycline is broadly protective in neurologic disease models featuring cell death and is being evaluated in clinical trials. We previously demonstrated that minocycline-mediated protection against caspase-dependent cell death related to its ability to prevent mitochondrial cytochrome c release. These results do not explain whether or how minocycline protects against caspaseindependent cell death. Furthermore, there is no information on whether Smac/Diablo or apoptosis-inducing factor might play a role in chronic neurodegeneration. In a striatal cell model of Huntington's disease and in R6/2 mice, we demonstrate the association of cell death/disease progression with the recruitment of mitochondrial caspase-independent (apoptosis-inducing factor) and caspase-dependent (Smac/Diablo and cytochrome c) triggers. We show that minocycline is a drug that directly inhibits both caspase-independent and -dependent mitochondrial cell death pathways. Furthermore, this report demonstrates recruitment of Smac/Diablo and apoptosis-inducing factor in chronic neurodegeneration. Our results further delineate the mechanism by which minocycline mediates its remarkably broad neuroprotective effects. [ABSTRACT FROM AUTHOR]