The precise molecular pathways leading to degeneration of motor neurons in ALS is not known , but as with other neurodegenerative diseases , is likely to be a complex interaction between the various cellular pathogenic mechanisms may not be mutually exclusive include :
1 . Genetic factors
Sporadic and familial ALS are clinically and pathologically similar , so there the possibility of having the same pathogenesis . Although only 2 % of patients with ALS have mutations in SOD1 , the discovery of these mutations are important in the study of ALS because it allows molecular -based research in the pathogenesis of ALS . SOD1 , is an enzyme that requires copper , catalyze the conversion of toxic superoxide radicals into hydrogen peroxide and oxygen . Copper atoms mediate catalysis processes that occur . SOD1 also has the ability pro-oxidation , including peroxidation , hydroxyl radical formation , and tyrosine nitration . Mutations in SOD1 that disrupt the function of antioxidants leads to accumulation of toxic superoxide . Hypothesis decreased function as a cause of the disease was not proven because overexpression of SOD1 mutant ( in which alanine substituting glycine at position 93 of SOD1 ( G93A ) cause motor neuron disease despite the absence of an increase in SOD1 activity . therefore , SOD1 mutations cause disease by disrupting the function of toxicity , not because of a decrease in SOD1 activity .
2 . excitotoxicity
It is a term for an injury caused by stimulation of neuronal
Excessive glutamate induced postsynaptic glutamate receptor cell surface receptors such as NMDA and AMPA receptors . This excessive stimulation of glutamate receptors thought to lead to an influx of calcium into the large neurons , which causes the formation of nitric oxide and thus increase neuronal death . Glutamate levels in CSF are increased in some patients with ALS . This elevation has been associated with cell loss of glial excitatory amino acid transporter EAAT2 .
3 . Oxidative stress
Oxidative stress has long been associated with several neuro degenerative and
it is known that the accumulation of reactive oxygen species ( ROS ) leading to cell death . Such as mutations in the superoxide dismutase enzyme anti - oxidant 1 ( SOD1 ) gene can cause ALS , there is significant interest in the mechanisms underlying the neurodegenerative process in ALS . This hypothesis is supported by the findings of biochemical changes that reflect free radical damage and abnormal metabolism of free radicals in tissue and post- mortem CSF samples of patients
4 . mitochondrial dysfunction
Mitochondrial morphology and biochemical abnormalities have been reported in patients with ALS .
Mitochondria from ALS patients showed high levels of calcium and decrease
activities of respiratory chain complexes I and IV , which involves the inability of energy metabolism .
5 . Impaired axonal transport
Axons of motor neurons can reach up to one meter in length in humans , and relying on efficient intracellular transport system . This system consists of anterograde transport system ( slow and fast ) and retrograde , and depends on the molecular 'motor ' kinesin protein complexes ( for anterograde ) and dynein - dynactin complex ( for retrograde ) . In patients with ALS , mutations in kinesin gene , known to cause motor neuron diseases in humans such as neurodegenerative hereditary spastic paraplegia and type 2A disease Charcot - Marie - Tooth . Mutation in dynactin complex cause lower motor neurons with vocal cord paralysis in humans .
6 . aggregation of neurofilament
Neurofilament protein together with Peripherin ( a protein filament
intermediates ) are found in most of the motor neurons of ALS patients axonal inclusions . A toxic peripherin isoform ( peripherin 61 ) , has been found to be toxic to motor neurons even when expressed at a modest rate and detected in the spinal cord of ALS patients but not controls
7 . protein aggregation
Intra - cytoplasmic inclusions are a hallmark of sporadic and familial ALS . However , it remains unclear , whether the aggregate pebentukkan directly cause cellular toxicity and has a key role in the pathogenesis , if the aggregate may be engaged by the product of the process of neurodegeneration , or if the aggregate formation might actually be a beneficial process to become part of a defense mechanism to reduce intracellular concentration of toxic protein
8 . Inflammatory dysfunction and contribution of non -neuronal cells
Although ALS is not a primary autoimmune disorders or immune dysregulation , there is considerable evidence that inflammatory processes and non-neuronal cells may play a role in the pathogenesis of ALS . Activation of microglial cells and dendritic pathology is prominent in human ALS and SOD1 transgenic mice . Non - activated nerve cells produce inflammatory cytokines such as interleukin , COX - 2 , TNFa and MCP - 1 , and upregulation of evidence or the CSF specimen was found in the spinal cord of ALS patients or in vitro models .
9. Deficits in neurotrophic factors and signaling pathways dysfunction
Decreased levels of neurotrophic factors (eg CTNF, BDNF, GDNF and IGF-1)
has been observed in ALS patients post-mortem and in in vitro models. In humans, mutations in three genes VEGF were found associated with an increased risk of developing sporadic ALS, although this meta-analysis by the same authors failed to show an association between VEGF haplotypes and increase the risk of ALS in humans. Final process of neuronal cell death in ALS allegedly similar programmed cell death pathway (apoptosis). Biochemical markers of apoptosis were detected in the terminal stage of ALS patients.