N-terminal kinase-like protein

SCYL1 (Q96KG9) is a multifunctional N-terminal kinase-like protein involved in intracellular membrane trafficking and transcriptional regulation. It regulates COPI-mediated retrograde protein transport between the Golgi apparatus and endoplasmic reticulum, maintaining Golgi morphology, and acts as a transcriptional activator binding GC-rich DNA sites in promoter regions including those of beta-polymerase and TERT (UniProt: Q96KG9).

The protein is involved in cellular compartmentalization and membrane homeostasis. Mutations in SCYL1 cause spinocerebellar ataxia, autosomal recessive, 21 (SCAR21; MIM 616719), characterized by early-onset cerebellar atrophy, ataxia, recurrent liver failure, and peripheral neuropathy (UniProt: Q96KG9).

In Alzheimer's disease, SCYL1 is significantly down-regulated in post-mortem AD brain compared to age-matched controls, with a mean log2 fold-change of −1.737 in human TMT-labeled proteomics of four subcellular fractions (Chaparral AD proteomics). This reduction may reflect disrupted Golgi-endoplasmic reticulum trafficking homeostasis in AD neurodegeneration.