Cells In Amyotrophic Lateral Sclerosis Research Articles

Ubiquitin and neurofilament expression in anterior horn cells in amyotrophic lateral sclerosis: possible clues to the pathogenesis.

Cytoskeletal abnormalities are a prominent pathological feature of anterior horn cells in amyotrophic lateral sclerosis (ALS), and are thought to be involved in the process of motor neuron death. Skein-like filamentous inclusions have been detected by immunocytochemical staining for ubiquitin, a stress protein involved in targeting abnormal proteins for proteolysis. So far, identification of the target protein has been elusive. We have studied the ultrastructural localization of ubiquitin and neurofilaments by post-embedding immunogold staining. In skein-like arrays, strong ubiquitin labelling was concentrated on abnormally formed 15-20 nm filaments; neurofilament labelling was localized on 10 nm filaments adjacent or in continuity with the abnormal filaments. In addition, Bunina bodies were a major site of ubiquitin accumulation. Our results suggest that ubiquitinated filaments in skein-like inclusions might originate from abnormally aggregated neurofilament proteins, which are no longer recognized by antibodies to neurofilament epitopes. Furthermore, the presence of ubiquitin in Bunina bodies suggests that, in addition to its protective role, ubiquitin might be directly implicated in the mechanism of programmed neuronal death in ALS.

Nerve growth factor receptor immunostaining in the spinal cord and peripheral nerves in amyotrophic lateral sclerosis

In animal experiments, nerve transection is followed by expression of nerve growth factor receptors (NGFR) on Schwann cells of both motor and sensory nerve fibres distally to the site of the lesion. To determine whether denervated Schwann cells in amyotrophic lateral sclerosis (ALS) similarly express NGFR, a study was made of post-mortem material of peripheral nerves and ventral roots from ALS cases and age-matched controls, using immunolabelling methods. Dorsal roots and spinal cords were also examined for the presence of NGFR. In all the ALS cases and controls, NGFR immunostaining was seen in the outer layer of vessel walls, perineurial sheaths, connective tissue surrounding fascicles in nerve roots and in the substantia gelatinosa of the spinal cord. In ALS, NGFR staining was also present in the Schwann cells of degenerated nerve fibres in mixed peripheral nerves, in ventral roots and, to a lesser extent, in dorsal roots. NGFR immunoreactivity was also seen in elongated cells extending from the perifascicular connective tissue into the nerve fascicles. It is concluded that denervated Schwann cells in ALS express NGFR and that NGFR immunostaining on Schwann cells may be used as an indicator of axonal degeneration. The NGFR labelling in the dorsal roots supports the notion that ALS is not a pure motor syndrome.

Deficient DNA repair in amyotrophic lateral sclerosis cells

We studied survival and DNA repair capacity in cultured sporadic ALS and control skin fibroblasts after treatment with DNA damaging agents producing different types of lesions. Mean survival in ALS and control fibroblasts was similar after exposure to ultraviolet (UV) light, x-rays and mitomycin C (MMC). Both mean survival and mean unscheduled (repair) DNA synthesis (UDS) were significantly reduced in ALS fibroblasts following treatment with the alkylating agent methyl methane sulfonate (MMS). These data suggest that ALS cells are relatively deficient in the repair of alkylation damage, possibly of apurinic/apyrimidinic sites, and that they are not unduly sensitive to DNA damage produced by UV light, x-rays and MMC. Normal survival and UDS seen in some patients' cells after MMS treatment indicate a spectrum of repair efficiency, and suggest heterogeneity of the biochemical defect in ALS.

Low percentage of Tμ cells in amyotrophic lateral sclerosis

The percentage of Tμ cells in amyotrophic lateral sclerosis patients is markedly reduced. The Tγ population appears normal.