Genetic Background Effects on Disease Onset and Lifespan of the Mutant Dynactin p150Glued Mouse Model of Motor Neuron Disease

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily affecting motor neurons in the central nervous system. Although most cases of ALS are sporadic, about 5–10% of cases are familial (FALS) with approximately 20% of FALS caused by mutations in the Cu/Zn superoxide dismutase (SOD1) gene. We have reported that hSOD1-G93A transgenic mice modeling this disease show a more severe phenotype when the transgene is bred on a pure SJL background and a milder phenotype when bred on a pure B6 background and that these phenotype differences link to a region on mouse Chromosome 17.To examine whether other models of motor neuron degeneration are affected by genetic background, we bred the mutant human dynactin p150Glued (G59S-hDCTN1) transgene onto inbred SJL and B6 congenic lines. This model is based on an autosomal dominant lower motor neuron disease in humans linked to a mutation in the p150Glued subunit of the dynactin complex. As seen in hSOD1-G93A mice, we observed a more severe phenotype with earlier disease onset (p<0.001) and decreased survival (p<0.00001) when the G59S-hDCTN1 transgene was bred onto the SJL background and delayed onset (p<0.0001) with increased survival (p<0.00001) when bred onto the B6 background. Furthermore, B6 mice with an SJL derived chromosome 17 interval previously shown to delay disease onset in hSOD1-G93A mice also showed delays onset in G59S-hDCTN1 mice suggesting that at least some genetic modifiers are shared. We have shown that genetic background influences phenotype in G59S-hDCTN1 mice, in part through a region of chromosome 17 similar to the G93-hSOD1 ALS mouse model. These results support the presence of genetic modifiers in both these models some of which may be shared. Identification of these modifiers will highlight intracellular pathways involved in motor neuron disease and provide new therapeutic targets that may be applicable to motor neuron degeneration.

Construction and Identification of a Novel 5-Gene Signature for Predicting the Prognosis in Breast Cancer

“…This gene is located on chromosome 12q13-q15, which is a region prone to stable amplification in many cancers. The DCTN family has been linked to neurodegeneration (14,15), and more and more studies have shown that DCTN2 may be a potential prognostic biomarker for cancer, including cutaneous melanoma, colon adenocarcinoma, and osteosarcoma (16)(17)(18). FK506-binding protein 14 (FKBP14) belongs to the FK506binding protein family.…”

Distinct prognostic value of dynactin subunit 4 (DCTN4) and diagnostic value of DCTN1, DCTN2, and DCTN4 in colon adenocarcinoma

“…DCTN1 is considered the largest subunit of dynactin, 23 and DCTN1 has been implicated in many neurodegenerative diseases. 10 – 12 DCTN2 connects with DCTN1 and DCTN3 to form a complex subunit. 23 DCTN4 was found to be associated with Wilson’s disease 24 and chronic Pseudomonas aeruginosa infection.…”

“…Previous research found that the DCTN family is linked with multiple neurodegenerative diseases. 10 – 12 Nevertheless, after bibliographic retrieval, it was found that only a few studies stated the correlation between the DCTN family and the prognosis and diagnosis of COAD.…”

Genetic background modifies amyloidosis in a mouse model of ATTR neuropathy

“…In the present study we examined the effects of different genetic backgrounds on amyloid deposition and various related molecular pathogenic markers in a transgenic model of ATTRV30M. Genetic background has previously been shown to affect the phenotype and severity of other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) [15] , [16] , [17] . Considering that the two lines of mice used in the current study bear the same mutation with regards to the disease-causing locus, our results suggest that genetic modifiers affect disease progression, or in this case, amyloid deposition.…”