Self-replicating Proteins: Final Common Pathways Leading to the Occurrence of Sporadic ALS
Objective:
Generate preliminary data in support of the notion that self-replicating proteins are the etiologic basis for Sporadic ALS.
Background:
The realization that co-morbidities involving interactions between proteins are common features of neurodegenerative diseases has disrupted traditional dogma regarding the pathogenesis of these disorders. To date, a similar evolution of thinking has not occurred in the instance of ALS.
Design/Methods:
Fluorescent dye and recombinant alpha-synuclein is added to each test well of a plastic plate followed by the addition of CSF. Following cycles of repeated shaking, Thioflavin T fluorescence is measured daily for 9 days using a microplate reader with an excitation wavelength of 440 nm and emission wavelength of 490 nm. If at least two out of three of the wells for each sample yield a fluorescent value greater than or equal to 25,000 relative fluorescence units, the sample is determined to be positive for misfolded α-Syn.
Results:
Toxic species of α-Syn were detected in CSF in 18 of 127 ALS patients, 5 of whom were from Guam. Positive seed-amplification assays (SAAs) were noted in 2 of 26 samples from patients with C9orf72 ALS. No positive tests were observed in SOD1 ALS subjects (n= 14) or in 31 control subjects. A subset of ALS cases (n=28), provided by the Barrow Neurological Institute were positive for either Lewy Bodies or Lewy neurites. In 4 of 6 of these self-replicating α-Syn was detected utilizing the SAA.
Conclusions:
The use of SAAs provides a window in to the etiology of Sporadic ALS leading to the conclusion that self-replicating proteins such as alpha-synuclein and other proteins (TDP-43, etc.) are the downstream abnormalities that are responsible for the most common variant of ALS. Hence forth, emphasis should be placed on the development SAAs and understanding the factors that lead to misfolding of cellular proteins.
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