The G336S Variant in the Human Neurofilament-M Gene Does Not Affect Its Assembly or Distribution: Importance of the Functional Analysis of Neurofilament Variants

• Published in: Journal of neuropathology and experimental neurology 2004-07, Vol.63 (7), p.759-774
• Main Authors: PEREZ-OLLE, RAUL, LOPEZ-TOLEDANO, MIGUEL A, LIEM, RONALD K.H
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Amyloid beta-Protein Precursor - metabolism; Biological and medical sciences; Brain - metabolism; Brain - pathology; Brain - physiopathology; Cell Line, Tumor; Cyclin-Dependent Kinase 5; Cyclin-Dependent Kinases - metabolism; DNA Mutational Analysis; DNA, Complementary - analysis; DNA, Complementary - genetics; Genetic Predisposition to Disease; Humans; Lewy Bodies - genetics; Lewy Bodies - metabolism; Lewy Bodies - pathology; Medical sciences; Mitochondria - genetics; Mitochondria - metabolism; Mutation - genetics; Neurofilament Proteins - biosynthesis; Neurofilament Proteins - genetics; Neurology; Neurons - metabolism; Neurons - pathology; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Polymorphism, Genetic - genetics; Protein Transport - genetics
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1093/jnen/63.7.759

The human neurofilament medium (hNFM) subunit is one of the 3 neurofilament (NF) polypeptides, which are the most abundant intermediate filament (IF) proteins in post-mitotic neurons. The formation of neurofilamentous aggregates is a pathological hallmark of many neurodegenerative diseases, including the Lewy bodies found in Parkinson disease (PD). A Gly336Ser (G336S) variant in the rod domain of hNFM has recently been described in a patient with early-onset autosomal-dominant PD. In this study, we have generated a mammalian expression vector encoding the variant hNFM cDNA and characterized its effects on the formation of heteropolymeric IFs in heterologous cell lines. We have also investigated the distribution of the (G336S) hNFM variant protein in neuronal CAD cells, as well as the effects of the variant on the distribution of other cellular organelles and proteins. Our results demonstrate that the G336S variant does not affect the formation of IF networks nor the distribution of the variant hNFM protein. Our data suggest that if the G336S variant is involved in the development of PD, it does not appear to be due to defects in the assembly and distribution of NFs.