Defective axonal transport of neurofilament proteins in neurons overexpressing peripherin

Abstract

Peripherin is a type III neuronal intermediate filament detected in motor neuron inclusions of amyotrophic lateral sclerosis (ALS) patients. We previously reported that overexpression of peripherin provokes late-onset motor neuron dysfunction in transgenic mice. Here, we show that peripherin overexpression slows down axonal transport of neurofilament (NF) proteins, and that the transport defect precedes by several months the appearance of axonal spheroids in adult mice. Defective NF transport by peripherin up-regulation was further confirmed with dorsal root ganglia (DRG) neurons cultured from peripherin transgenic embryos. Immunofluorescence microscopy and western blotting revealed that excess peripherin provokes reduction in levels of hyperphosphorylated NF-H species in DRG neurites. Similarly the transport of a green fluorescent protein (GFP)-tagged NF-M, delivered by means of a lentiviral construct, was impaired in DRG neurites overexpressing peripherin. These results demonstrate that peripherin overexpression can cause defective transport of type IV NF proteins, a phenomenon that may account for the progressive formation of ALS-like spheroids in axons.

Conditional NF-L Transgene Expression in Mice forIn VivoAnalysis of Turnover and Transport Rate of Neurofilaments

“…Thus, the stationary NFs network is a determinant of half-life and axonal transport rate of NF-L proteins. (Collard et al, 1995;Marszalek et al, 1996;Xu and Tung, 2000) as well as by excess of peripherin (Millecamps et al, 2006). NF transport in the sciatic nerve was found to be increased after NF-H or NF-M deletion (Zhu et al, 1998;Jacomy et al, 1999).…”

Protein Kinase Cϵ Binds Peripherin and Induces Its Aggregation, Which Is Accompanied by Apoptosis of Neuroblastoma Cells

“…Transgenic mice that overexpress peripherin exhibit motor neuron loss that is preceded by the appearance of peripherin inclusions in the cells (12,13) and by defective axonal transport (14). Furthermore, the aggregation of peripherin makes neurons more susceptible to cell death stimuli (12), suggesting a causal link between the formation of aggregates and cellular degeneration.…”

Les dys-fonctionnements du transport axonal dans les neuropathies et motoneuronopathies

“…Or, la surproduction de péri-phérine est toxique pour les motoneurones, comme on a pu le constater chez la souris [18]. Chez cet animal, une altération du transport axonal précède l'apparition d'agrégats, appelés sphéroïdes, qui s'accumulent dans les axones [19]. Une forme particulière de SLA associant une démence frontotemporale et un syndrome parkinsonien est liée à des mutations dans le gène codant la protéine Tau [20].…”