TABLE 1.

Examples of Proteins Implicated in Normal Nervous System Development and Late-Life Neurodegenerative Disease

Disease	Protein	Putative Function in Normal Nervous System Development	Putative Role in Disease Pathogenesis and/or Progression
Alzheimer disease	Aβ	Proliferation and differentiation of neural stem cells; neuronal migration, neurite outgrowth, and synaptogenesis; neuronal plasticity and learning; cell signaling receptor; binding partner of N-methyl-D-aspartate receptor	Activates Wnt signaling and thereby enhances proliferation of neural stem cells and inhibits their differentiation; generates intracellular C-terminal domain which translocates to the nucleus and transcriptionally represses the canonical, β-catenin‐dependent branch of the Wnt signaling pathway; modulates Notch signaling; inhibits Shh signaling
	Rac1	Dendritogenesis	Cytoplasmic translocation of SET, decreased activity of protein phosphatase 2A, and consequent accumulation of hyperphosphorylated tau
	MAPT/tau	Maturational predominant localization to and dephosphorylation in axons	Persistence of diffuse cellular localization and phosphorylation with loss of dendritic spines
Frontotemporal dementia	Progranulin	Plays role in lysosomal protein trafficking	Homozygous or compound heterozygous mutations lead to neuronal ceroid lipofuscinosis (CLN11 type); hemizygous mutations lead to frontotemporal dementia
Huntington disease	Huntingtin	Unknown (knockout or trinucleotide repeat = embryonic lethal)	Degeneration of medium spiny neurons and gliosis in striatum and cerebral cortex
Parkinson disease	Glucocerebrosidase	Lysosomal glycoside hydrolase that cleaves the glycolipid glucosylceramide	Homozygous or compound heterozygous mutations lead to the lysosomal storage disorder, Gaucher disease; hemizygous mutations predispose to Parkinson disease and Lewy body dementia, mechanism unknown; possibly related to generalized decrease in lysosomal function with consequent accumulation of α-synuclein; impaired mitochondrial autophagy; misfolded glucocerebrosidase with consequent impairment of Parkin ubiquitin lyase function and accumulation of protein aggregates and damaged mitochondria
	PINK, Parkin	PINK: mitochondrial serine/threonine kinase important for oxidative phosphorylation; Parkin: ubiquitin lyase that earmarks damaged mitochondria for destruction	Mutations of PINK or uncoupling of oxidative phosphorylation inactivate PINK preventing it from “attracting” Parkin and causing it to accumulate in the mitochondrial membrane; mutations of Parkin cause damaged mitochondria to accumulate; Parkin mutations are seen in juvenile Parkinson disease