The child is father to the man: developmental roles for proteins of importance for neurodegenerative disease

Abstract

Although Alzheimer's and Parkinson's diseases predominately affect elderly adults, the proteins that play a role in the pathogenesis of these diseases are expressed throughout life. In fact, many of the proteins hypothesized to be important in the progression of neurodegeneration play direct or indirect roles in the development of the central nervous system. The systems affected by these proteins include neural stem cell fate decisions, neuronal differentiation, cellular migration, protection from oxidative stress, and programmed cell death. Insights into the developmental roles of these proteins may ultimately impact the understanding of neurodegenerative diseases and lead to the discovery of novel treatments.

FIGURE 1

Protein cleavage by γ-secretase results in downstream signaling purported to be of relevance for Alzheimer’s disease and development of the central nervous system. APP = amyloid precursor protein; ApoE = apolipoprotein E; NGF = nerve growth factor; NICD = Notch intracellular domain; PS1 = Presenilin-1; p75ICD = p75 intracellular domain; VLDLR = very-low-density lipoprotein receptor; ApoER2 = apolipoprotein E receptor 2; CTF = C-terminal fragment.

FIGURE 2

Developmentally important pathways involving cellular protein degradation, antioxidant reserve, and life-and-death decision making have been implicated in the pathogenesis of Parkinson’s disease. LRRK2 = leucine-rich repeat kinase 2; PINK1 = PTEN-induced kinase 1; UCH-L1 = ubiquitin C-terminal hydrolase L1.