IAP family proteins delay motoneuron cell death in vivo

Abstract

Neuronal apoptosis inhibitory protein (NAIP), and human inhibitors of apoptosis 1 and 2 (HIAP1 and HIAP2) are three members of the mammalian family of antiapoptosis proteins called 'inhibitors of apoptosis' (IAP). These molecules can prevent apoptosis in vitro and the over-expression of NAIP can decrease ischemic damage in the hippocampus. The goal of our experiments was to determine whether administration of NAIP, HIAP1 and HAIP2 could rescue motoneurons following axotomy of a peripheral nerve. In young rats, an adenoviral gene transfer technique was used to deliver and express these proteins in motoneurons; a fluorescent tracer was simultaneously added as a means for quantitatively assessing the rescue of fluorescently labelled motoneurons in serial sections of the lumbar spinal cord. Control experiments using adenoviral vectors (adv) expressing the lacZ gene showed that 14% of the sciatic motoneuron pool could be transfected indicating the existence of a subpopulation of spinal motoneurons susceptible to this class of viral vectors. The administration of an adv-NAIP, adv-HIAP1 and adv-HIAP2 rescued 30-40% of motoneurons at one week after sciatic axotomy. The efficiency of these proteins was similar to that of two neurotrophic factors, ciliary neurotrophic factor and brain-derived neurotrophic factor, administrated by the same viral technique. The effect of the IAP proteins on motoneuron survival decreased with time but was still present after 4 weeks postaxotomy; the duration of the response was dependent upon the viral titre. These experiments demonstrate that IAP family proteins can prevent motoneuron cell death in vivo and may offer a new therapeutic approach for motoneuron diseases.

The Neuronal Apoptosis Inhibitory Protein Is a Direct Inhibitor of Caspases 3 and 7

“…A number of laboratories have shown that NAIP is antiapoptotic and cytoprotective in a variety of cellular and in vivo models (Liston et al, 1996;Xu et al, 1997;Perrelet et al, 2000), suggesting that NAIP is an important regulator of neuronal apoptosis. However, a mechanism of NAIP action has not yet been described.…”

The inhibitors of apoptosis: there is more to life than Bcl2

“…Perhaps most significantly, functional rescue of memory and learning ability was demonstrated (Xu et al, 1997. Adenoviral vectors encoding NAIP, c-IAP1, and c-IAP2 have been shown to suppress apoptosis in the sciatic nerve axotomy model (Perrelet et al, 2000(Perrelet et al, , 2002, and adeno-XIAP in an optic nerve axotomy model (Kugler et al, 2000). Additionally, NAIP overexpression has been shown to be protective both histologically and functionally in the 6-hydroxydopamine model of Parkinson's disease (Crocker et al, 2001).…”

Highly Efficient Retrograde Gene Transfer for Genetic Treatment of Neurological Diseases

“…Motor neurons are the target for gene therapy of motor neuron diseases (Baumgartner & Shine, 1998;Perrelet et al, 2000;Mazarakis et al, 2001;Sakamoto et al, 2003;Azzouz et al, 2004b). Therefore, we studied retrograde gene transfer of the HiRet vector into motor neurons in the hindbrain and spinal cord.…”

“…These viral vectors, when injected into the striatum, deliver the genes through retrograde transport into nigrostriatal dopamine neurons that are the major target for gene therapy of Parkinson's disease (Zheng et al, 2005;Barkats et al, 2006). Intramuscular injection of the vectors also delivers retrogradely the genes into motor neurons that are the target for gene therapy of motor neuron diseases (Baumgartner & Shine, 1998;Perrelet et al, 2000;Mazarakis et al, 2001;Sakamoto et al, 2003;Azzouz et al, 2004b). To enhance the gene transfer of a human immunodeficiency virus type-1 (HIV-1)-based vector via retrograde transport, we have previously generated the HIV-1 vector pseudotyped with a selective variant of rabies virus glycoprotein (RV-G) (Kato et al, 2007).…”