Impaired autophagy: The collateral damage of lysosomal storage disorders

Abstract

Lysosomal storage disorders (LSDs), which number over fifty, are monogenically inherited and caused by mutations in genes encoding proteins that are involved in lysosomal function. Lack of the functional protein results in storage of a distinctive material within the lysosomes, which for years was thought to determine the pathophysiology of the disorder. However, our current view posits that the primary storage material disrupts the normal role of the lysosome in the autophagic pathway resulting in the secondary storage of autophagic debris. It is this "collateral damage" which is common to the LSDs but nonetheless intricately nuanced in each. We have selected five LSDs resulting from defective proteins that govern widely different lysosomal functions including glycogen degradation (Pompe), lysosomal transport (Cystinosis), lysosomal trafficking (Danon), glycolipid degradation (Gaucher) and an unidentified function (Batten) and argue that despite the disparate functions, these proteins, when mutant, all impair the autophagic process uniquely.

Keywords: Autophagy; Batten disease; Cystinosis; Danon disease; Gaucher disease; Lysosome; Pompe disease.

Fig. 1

Three types of autophagy. All three types – macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) – converge on the lysosome. HSC70: heat shock-cognate chaperone 70 KDa protein; LAMP2A: lysosome-associated membrane protein 2 isoform A.

Fig. 2

Localization of affected proteins involved in five LSDs and their impact on autophagy. GAA: acid alpha-glucosidase; CLN: ceroid lipofuscinosis neuronal; LAMP: lysosome-associated membrane protein; CMA: chaperone-mediated autophagy; GCase: glucocerebrosidase; Cer: ceramide; Sph: sphingosine. The dashed blue line indicates the link between cystinosin and CMA; LIMP-2 is a receptor for GCase.