Detergent‐insoluble inclusion constitutes the first pathology in PFN1 transgenic rats

Abstract

Mutation of profilin 1 (PFN1) can cause amyotrophic lateral sclerosis (ALS). To assess how PFN1 mutation causes the disease, we created transgenic rats with human genomic DNA that harbors both the coding and the regulatory sequences of the human PFN1 gene. Selected transgenic lines expressed human PFN1 with or without the pathogenic mutation C71G at a moderate and a comparable level and in the similar pattern of spatial and temporal expression to rat endogenous PFN1. The artificial effects of arbitrary transgene expression commonly observed in cDNA transgenic animals were minimized in PFN1 transgenic rats. Expression of the mutant, but not the wild type, human PFN1 in rats recapitulated the cardinal features of ALS including the progressive loss of motor neurons and the subsequent denervation atrophy of skeletal muscles. Detergent-insoluble PFN1 inclusions were detected as the first pathology in otherwise asymptomatic transgenic rats expressing mutant human PFN1.The findings suggest that protein aggregation is involved in the neurodegeneration of ALS associated with PFN1 mutation. The resulting rat model is useful to mechanistic study on the ALS.

The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis

“…Other transgenic mouse models expressing strong levels of C71G or G118V mutant PFN1, under the control of neuronal Thy1.2 or PrP promoters, showed strong motor phenotypes and decreased survival, and loss of motor neurons in the spinal cord, resembling ALS [ 22 , 23 , 24 , 25 ]. We did not observe a strong disease phenotype using our lentiviral transgenesis approach based on the expression of PFN1 under the control of the human ubiquitin C promoter.…”

“…Whether PFN1 mutations contribute to an ALS phenotype through a gain- or a loss-of-function is a source of debate [ 2 , 13 , 21 ]. However, the evidence supporting a gain-of-function mechanism is far more robust, since the transgenic rodents expressing mutant (C71G, G118V) PFN1 forms elicit motor neuron degeneration and ALS-like phenotypes [ 22 , 23 , 24 , 25 ], whereas heterozygous Pfn1 knockout mice do not show overt motor phenotypes [ 26 ].…”

Profilin Isoforms in Health and Disease – All the Same but Different

“…Exome sequencing studies reveal 8 mutations in the PFN1 gene in both familial and sporadic ALS cases (C71G, G118V, M114T, E117G, T109M, R136W, A20T, Q139L) (Figure 6.1; Wu et al, 2012;Chen et al, 2013;Ingre et al, 2013;Smith et al, 2015;Alkam et al, 2017). The PFN1-associated ALS pathology is reproducible in several mouse and rat models (Yang et al, 2016;Fil et al, 2017;Barham et al, 2018;Brettle et al, 2019;Yuan et al, 2020). The expression of ALS-PFN1 mutants evokes cytoskeletal and morphological defects in primary neurons, such as abnormally low ratios of F-/G-actin, shorter dendrites and integrity-impaired axons, which undergo Wallerian degeneration over time (Figure 6.2; Wu et al, 2012;Yang et al, 2016;Fil et al, 2017).…”

Profilin—A master coordinator of actin and microtubule organization in mammalian cells

“…Importantly this paper also showed that profilin has the capacity to directly bind microtubules in vitro in an interaction independent of either the actin or PLP‐binding surfaces but compromised by ALS‐related mutations characterized previously (Wu et al, 2012). Current studies in this area are now focused to understand how the profile of this devastating disease correlates with an inability of profilin to directly associate with microtubules (e.g., Brettle et al, 2019; Yuan et al, 2020).…”