Gene Expressions Specifically Detected in Motor Neurons (Dynactin 1, Early Growth Response 3, Acetyl-CoA Transporter, Death Receptor 5, and Cyclin C) Differentially Correlate to Pathologic Markers in Sporadic Amyotrophic Lateral Sclerosis

Abstract

In a differential gene expression profile, we showed previously that dynactin 1 (DCTN1), early growth response 3 (EGR3), acetyl-CoA transporter (ACATN), death receptor 5 (DR5), and cyclin C (CCNC) were prominently up- or downregulated in motor neurons of sporadic amyotrophic lateral sclerosis (ALS). In the present study, we examined the correlation between the expression levels of these genes and the levels of pathologic markers for motor neuron degeneration (i.e. cytoplasmic accumulation of phosphorylated neurofilament H [pNF-H] and ubiquitylated protein) and the numbers of residual motor neurons in 20 autopsies of patients with sporadic ALS. DCTN1 and EGR3 were widely downregulated, and the changes in gene expression were correlated to the number of residual motor neurons. In particular, DCTN1 was markedly downregulated in most residual motor neurons before the accumulation of pNF-H, even in cases with well-preserved motor neuron populations. ACATN, DR5, and CCNC were upregulated in subpopulations of residual motor neurons, and their expression levels were well correlated with the levels of pNF-H accumulation and the number of residual motor neurons. The expressions of DCTN1, EGR3, ACATN, and DR5 were all markedly altered before ubiquitylated protein accumulation. DCTN1 downregulation appears to be an early event before the appearance of neurodegeneration markers, whereas upregulations of DR5 and CCNC are relatively later phenomena associated with pathologic markers and leading to neuronal death. The sequence of motor neuron-specific gene expression changes in sporadic ALS can be beneficial information in developing appropriate therapeutic strategies for neurodegeneration.

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

“…Indeed, dysregulation in either the dynein-dynactin complex (LaMonte et al, 2002;Hafezparast et al, 2003) or peripherin (Beaulieu et al, 1999) causes spinal motor neuron degeneration in mice, presumably through defective axonal transport (LaMonte et al, 2002;Hafezparast et al, 2003;Millecamps et al, 2006). Furthermore, sALS patient spinal motor neurons show decreased levels of dynactin (Jiang et al, 2007). Our human tissue analyses showed that dynein was preferential to hypoglossal and spinal motor neurons in control patient tissues, while in ALS patients dynein was present at similar levels in all motor neuron groups.…”

Deregulated expression of cytoskeleton related genes in the spinal cord and sciatic nerve of presymptomatic SOD1G93A Amyotrophic Lateral Sclerosis mouse model

“…Mutation in Dctn1 gene has been associated to motor neuron degeneration in ALS (Hafezparast et al, 2003) and downregulation of the gene was described in residual motor neurons of postmortem material of ALS patients (Jiang et al, 2007). There is a lack of information on dynactin regulation before clinical onset of ALS despite the fact that dynein-dynactin complex, the only retrograde transport motor, contributes to formation of SOD1 inclusions in the disease (Strom et al, 2008).…”

AT-1 is the ER membrane acetyl-CoA transporter and is essential for cell viability

“…In fact, any result obtained with postmortem AD tissue is heavily influenced by the long duration of the disease, which could affect the genetic profile of the tissue. However, it is important to consider that AT-1 was also found upregulated in the motor neurons of ALS patients (Jiang et al, 2007), suggesting a possible involvement in general mechanisms involved with neurodegeneration. In fact, AD and ALS differ at the mechanistic level but share common disease-relevant features, such as disruption of axonal transport, synaptic-cargo impairment, disposal of aberrant protein aggregates and organelle damage (reviewed in De Vos et al, 2008;Wong et al, 2002).…”

“…Recent work has also shown that AT-1 is upregulated in motor neurons of patients affected by sporadic amyotrophic lateral sclerosis (ALS) (Jiang et al, 2007) and mutated in patients affected by autosomal dominant spastic paraplegia-42 (SPG42) (Lin et al, 2008), suggesting an implication in neurodegenerative disorders.…”