Non-neuronal cells such as microglia, astrocytes, and oligodendrocytesalso contribute to ALS pathogenesis, via alterations to the spinal cord microenvironment, increased glutamate excitotoxicity, and/or impaired neuronal metabolic support.
Furthermore, altered peripheral immunological responses and neuroinflammation are emerging as important effectors of the ALS disease course. Recent evidence has also linked protein aggregation and impaired RNA processing to ALS pathogenesis. Among the many proposed mechanisms for the more common sporadic form of ALS, oxidative stress and glutamate toxicity induce a toxic cellular and spinal cord milieu, respectively, while neurofilament aggregation and axonal transport defects may be associated with altered mitochondrial trafficking and impaired retrograde transport of peripherally-derived neurotrophic factors. Most recently, hexanucleotide repeat expansions in the 5’ noncoding region of the C9orf72 gene have been identified as the most common cause of familial ALS.
Several genetic mutations are associated with familial ALS, including mutations in Cu 2+/Zn 2+ superoxide dismutase (SOD1) and TAR DNA binding protein-43 (TDP-43). Only 10 to 15% of cases of ALS are familial, while the remaining 85 to 90% of cases are classified as sporadic. The development of targeted therapies for ALS, however, has been hindered by the fact that the mechanisms responsible for disease onset and progression largely remain unknown. Riluzole, the only FDA-approved treatment for ALS, extends survival for merely a few months, highlighting the need for more effective therapies. In almost all cases, death occurs within 3-5 years of diagnosis when progressive motor neuron degeneration affects the diaphragm and leads to respiratory failure. Sporadic and familial forms are clinically and pathologically indistinguishable, with symptoms including muscle weakness and atrophy that present in either bulbar muscles and/or in the limbs. Amyotrophic lateral sclerosis (ALS) is a lethal adult-onset neurodegenerative disorder characterized by the loss of both upper and lower motor neurons.
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