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Published on: October 3, 2011
X-Linked inhibitor of apoptosis protein gene-based neuroprotection for the peripheral nervous system
Mary E Garrity-Moses1, Qingshan Teng, Christina Krudy
1Cleveland Clinic Foundation, Lerner Research Institute, Department of Neuroscience and Center for Neurological Restoration, Cleveland, Ohio 44195, USA.
Objective:
The recently discovered X-linked inhibitor of apoptosis protein (XIAP) is among the most potent inhibitors of programmed cell death. In the current experiment, we examine the potential of adenoviral XIAP gene delivery to protect neurons of the peripheral nervous system using in vitro models of amyotrophic lateral sclerosis (ALS) and diabetic neuropathy.
Methods:
XIAP complementary deoxyribonucleic acid was fused in frame with the green fluorescent protein sequence and cloned into a first generation adenoviral vector. The impact of XIAP gene expression on glutamate-induced apoptosis was measured in the neuronal SH-SY5Y cell line with immunohistochemistry for active caspase-3 and with cell density assays. Next, the effect of XIAP expressing neurons on the survival of uninfected neighboring neurons was measured. Finally, the impact of XIAP gene expression on glutamate-induced apoptosis was assessed in embryonic motor neuron and dorsal root ganglion cultures.
Results:
XIAP gene expression reduced the percentage of active caspase-3 positive SH-SY5Y neurons and preserved cell density after glutamate exposure. In heterogeneously infected cultures, cells infected with XIAP were protected, but uninfected neighboring cells were not. In primary E15 models, inhibition of proapoptotic effects was demonstrated after glutamate insult in motor neurons and glucose insult in dorsal root ganglion cells.
Conclusion:
XIAP gene delivery through the neurosurgical delivery of viral vectors may provide a means for neuroprotection in ALS and diabetic neuropathy.
Insights
Adenoviral X-linked inhibitor of apoptosis protein (XIAP) gene delivery protected peripheral nervous system neurons in vitro. This neuroprotection strategy shows promise for treating neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and diabetic neuropathy.
Area of Science:
- Neuroscience
- Molecular Biology
- Gene Therapy
Background:
- Programmed cell death (apoptosis) is implicated in neurodegenerative diseases.
- X-linked inhibitor of apoptosis protein (XIAP) is a potent apoptosis inhibitor.
- Peripheral nervous system (PNS) neuron vulnerability in diseases like ALS and diabetic neuropathy.
Purpose of the Study:
- To investigate the neuroprotective potential of adenoviral XIAP gene delivery in vitro.
- To assess XIAP's efficacy in models of amyotrophic lateral sclerosis (ALS) and diabetic neuropathy.
Main Methods:
- Constructed an adenoviral vector expressing XIAP fused to green fluorescent protein.
- Evaluated glutamate-induced apoptosis in SH-SY5Y neuroblastoma cells using caspase-3 activity and cell density assays.
- Assessed XIAP's impact on primary motor neurons and dorsal root ganglion cultures.
Main Results:
- XIAP gene expression significantly reduced active caspase-3 and preserved cell density in SH-SY5Y cells post-glutamate exposure.
- XIAP conferred protection to infected cells, but not to neighboring uninfected cells.
- XIAP inhibited apoptosis in primary motor neurons (glutamate insult) and dorsal root ganglion cells (glucose insult).
Conclusions:
- Adenoviral XIAP gene delivery demonstrates significant neuroprotection in relevant in vitro models.
- Neurosurgical delivery of XIAP-expressing viral vectors offers a potential therapeutic strategy for ALS and diabetic neuropathy.
