Global gene expression profiling of somatic motor neuron populations with different vulnerability identify molecules and pathways of degeneration and protection

Abstract

Different somatic motor neuron subpopulations show a differential vulnerability to degeneration in diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy and spinobulbar muscular atrophy. Studies in mutant superoxide dismutase 1 over-expressing amyotrophic lateral sclerosis model mice indicate that initiation of disease is intrinsic to motor neurons, while progression is promoted by astrocytes and microglia. Therefore, analysis of the normal transcriptional profile of motor neurons displaying differential vulnerability to degeneration in motor neuron disease could give important clues to the mechanisms of relative vulnerability. Global gene expression profiling of motor neurons isolated by laser capture microdissection from three anatomical nuclei of the normal rat, oculomotor/trochlear (cranial nerve 3/4), hypoglossal (cranial nerve 12) and lateral motor column of the cervical spinal cord, displaying differential vulnerability to degeneration in motor neuron disorders, identified enriched transcripts for each neuronal subpopulation. There were striking differences in the regulation of genes involved in endoplasmatic reticulum and mitochondrial function, ubiquitination, apoptosis regulation, nitrogen metabolism, calcium regulation, transport, growth and RNA processing; cellular pathways that have been implicated in motor neuron diseases. Confirmation of genes of immediate biological interest identified differential localization of insulin-like growth factor II, guanine deaminase, peripherin, early growth response 1, soluble guanylate cyclase 1A3 and placental growth factor protein. Furthermore, the cranial nerve 3/4-restricted genes insulin-like growth factor II and guanine deaminase protected spinal motor neurons from glutamate-induced toxicity (P < 0.001, ANOVA), indicating that our approach can identify factors that protect or make neurons more susceptible to degeneration.

The Role of PSD-95 and Cypin in Morphological Changes in Dendrites Following Sublethal NMDA Exposure

“…Release of cypin from the neuron during and after NMDA treatment may lead to cell death since intracellular cypin appears to confer neuroprotection from this treatment. However, exogenously added cypin (guanine deaminase) protects spinal motor neurons from glutamate-induced toxicity (Hedlund et al, 2010). We added exogenous cypin to our cultures and observed no protection from NMDA-induced toxicity (data not shown).…”

Mitochondrial Oxidative Phosphorylation Transcriptome Alterations in Human Amyotrophic Lateral Sclerosis Spinal Cord and Blood

“…Interestingly, ocular motor neurons in normal human specimens and a pre-symptomatic rodent model of ALS show increased expression of nuclear-encoded genes related to mitochondrial OXPHOS (Brockington et al 2013) and function (Hedlund et al 2010) compared with spinal motor neurons. Neither of these studies measured mtDNA gene expression.…”

“…Many cellular processes are affected, resulting in protein misfolding, oxidative damage, altered DNA/RNA processing, defective axonal transport, excitotoxicity and inflammation. Mitochondrial dysfunction and defects in energy metabolism are believed to play an important part in ALS pathology as well (Dupuis et al 2011;Brockington et al 2013;Cassina et al 2008;Cozzolino and Carri 2012;Hedlund et al 2010;Heath et al 2013;Reddy and Reddy 2011).…”

Motor neurons with differential vulnerability to degeneration show distinct protein signatures in health and ALS

“…Importantly, in vivo and in vitro models of fALS indicate that factors intrinsic to motor neurons are crucial for initiation of degeneration (Boillee et al, 2006;Jaarsma et al, 2008;Huang et al, 2012;Kiskinis et al, 2014), while astrocytes and microglia drive disease progression (Boillee et al, 2006;Yamanaka et al, 2008;Das and Svendsen, 2014). It therefore seems that differential expression of factors intrinsic to motor neurons render these cells more or less vulnerable to toxic events (Saxena et al, 2009;Hedlund et al, 2010;Kaplan et al, 2014). Thus, identification of cell intrinsic mechanisms of protection and vulnerability may lead to therapies preventing the progressive loss of motor neurons.…”