Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, and Parkinson's disease are associated with the aggregation of the pathological proteins[1]. However, the mechanism behind and the contribution of protein aggregation to these diseases are yet to known. Recent years, many studies have shown that post translational modification(PTM) of these proteins at specific site potentially lead the pathological change[2] . Therefore, understanding the role of these PTM proteins are of great interests. To identify the structure, function, aggregation process, propagation properties, and thereby pathological significance of these PTM proteins, we synthesized Ser8-phosphorylated amyloid-b, Ser129-phosphorylated a-synuclein and Ser-404 phosphorylated TDP43 utilizing a native chemical ligation reaction between the N-terminal recombinant thioester protein and C-terminal site-specific modified peptide using solid phase peptide synthesis (SPPS). It was also confirmed in these works that phosphorylation of these proteins induces distinct aggregation strains and are functionally more toxic than the wild types. Evidence shown in these works strongly supported the view that PTM impact the pathological process of neurodegenerative diseases and give clues for future drug discovery[3].