Abstract
Neuronal ceroid lipofuscinosis (NCL) is a collection of genetically inherited neurological disorders characterized by vision loss, seizure, brain death, and premature lethality. At the cellular level, a key pathologic hallmark of NCL is the build-up of autofluorescent storage materials (AFSM) in lysosomes of both neurons and non-neuronal cells. Molecular dissection of the genetic lesions underlying NCLs has shed significant insights into how disruption of lysosomal homeostasis may lead to lipofuscin accumulation and NCLs. Intriguingly, recent studies on DNAJC5/CSPα, a membrane associated HSC70 co-chaperone, have unexpectedly linked lipofuscin accumulation to two intimately coupled protein quality control processes at endolysosomes. This review discusses how deregulation of unconventional protein secretion and endosomal microautophagy (eMI) contributes to lipofuscin accumulation and neurodegeneration.