We observed that a small group of ALS-linked miRNAs that are expressed in human spinal motor neurons directly regulate NEFM and NEFH transcript levels in a manner that is associated with an increase in NFM and NFH protein levels in ALS spinal cord homogenates.
Mutations in the NEFH gene encoding the heavy neurofilament protein are usually associated with neuronal damage and susceptibility to amyotrophic lateral sclerosis (ALS).
Variant filtering identified potentially deleterious mutations in three known disease genes: DCTN1, KIF5A and NEFH, which have been all associated with similar clinical presentations of amyotrophic lateral sclerosis, Parkinsonism and/or hereditary spastic paraplegia.
These results implicate Pin1 as a possible modulator of stress-induced NF-H phosphorylation as seen in neurodegenerative disorders like AD and amyotrophic lateral sclerosis.
Neurofilaments and peripherin appear to play some part in motor neuron degeneration, and amyotrophic lateral sclerosis is occasionally associated with mutations of the neurofilament heavy chain gene.
Cytoskeletal abnormalities have been reported in cases of amyotrophic lateral sclerosis (ALS) including abnormal inclusions containing neurofilaments (NFs) and/or peripherin, reduced mRNA levels for the NF light (NF-L) protein and mutations in the NF heavy (NF-H) gene.
The finding that extra NF-L can protect against NF-H-mediated pathogenesis is of potential importance for ALS, particularly for cases with NF-H abnormalities.
To investigate the role of neurofilaments in motor neuron disease caused by superoxide dismutase (SOD1) mutations, transgenic mice expressing a amyotrophic lateral sclerosis-linked SOD1 mutant (SOD1(G37R)) were mated with transgenic mice expressing human neurofilament heavy (NF-H) subunits.
To examine whether mutation in neurofilament subunits causes or predisposes to ALS, we used single-strand conformation polymorphism coupled with DNA sequencing to search for mutations in the entirety of the human NF-L, NF-M, and NF-H genes from 100 familial ALS patients known not to carry mutations in superoxide dismutase 1 (SOD1), as well as from 75 sporadic ALS patients.
First, transgenic mice that overexpress neurofilament proteins show motor neuron degeneration and, second, variant alleles of the neurofilament heavy-subunit gene (NF-H) have been found in some human ALS patients.
We propose that a modest up-regulation of NF-H cross-linkers can result in an impairment of neurofilament transport, causing neuronal swellings with ensuing axonopathy and muscle atrophy, a mechanism of pathogenesis pertinent to the possible etiology of ALS.