For example, the ER-Mito CSs can be down-regulated by mutations in LRRK2 or α-synuclein 20, 21, while up-regulated by the knockout of PINK1 or parkin in Parkinson's disease (PD) 22-24; upregulation of these CSs is also detected in Alzheimer's disease (AD) induced by the products of APP sequential cleavage in amyloidogenic processing, including its C-terminal fragments (APP-CTFs) generated by β-secretase 25 and β-amyloid peptide (Aβ) produced by further γ-secretase cleavage 26, 27. The gene discussed is APP; the disease is Alzheimer disease.