Mitochondrial dysfunction associated with glucocerebrosidase deficiency

Abstract

The lysosomal hydrolase glucocerebrosidase (GCase) is encoded for by the GBA gene. Homozygous GBA mutations cause Gaucher disease (GD), a lysosomal storage disorder. Furthermore, homozygous and heterozygous GBA mutations are numerically the greatest genetic risk factor for developing Parkinson's disease (PD), the second most common neurodegenerative disorder. The loss of GCase activity results in impairment of the autophagy-lysosome pathway (ALP), which is required for the degradation of macromolecules and damaged organelles. Aberrant protein handling of α-synuclein by the ALP occurs in both GD and PD. α-synuclein is the principle component of Lewy bodies, a defining hallmark of PD. Mitochondrial dysfunction is also observed in both GD and PD. In this review we will describe how mitochondria are affected following loss of GCase activity. The pathogenic mechanisms leading to mitochondria dysfunction will also be discussed, focusing on the likely inhibition of the degradation of mitochondria by the ALP, also termed mitophagy. Other pathogenic cellular processes associated with GBA mutations that might contribute, such as the unfolding of GCase in the endoplasmic reticulum, calcium dysregulation and neuroinflammation will also be described. Impairment of the ALP and mitochondria dysfunction are common pathogenic themes between GD and PD and probably explain why GBA mutations increase the risk of developing PD that is very similar to sporadic forms of the disease.

Keywords: Autophagy; Gaucher disease; Glucocerebrosidase; Lysosome; Mitochondria; Parkinson's disease; mitophagy.

Fig. 1

Macroautophagy and chaperone mediated autophagy pathways. (A) Macromolecules such as protein and lipids (green square), aggregated proteins (red fibrils) or damaged mitochondria (see inset) are recruited to phagophores by binding to LC3-II embedded in the membrane (orange segments). Phagophores mature into double membrane autophagosomes thus sequestering cargo for degradation. Following fusion with lysosomes to form an autolysosome, macromolecules and organelles are degraded by degradative enzymes from the lysosome. Inset: damaged mitochondria have decreased Ψm causing accumulation of full length PINK1 on the OMM. This recruits and phosphorylates the E3 ubiquitin ligase parkin (park) and ubiquitin (ubq; orange star), resulting in ubiquitination of proteins in the OMM (white cross). These proteins can then be bound by p62 (green teardrop) that enables binding to LC3-II on the phagophore. Other mitophagy receptors (white triangle) that can bind LC3-II such as FUNDC1, BNIP and cardiolipin are also up regulated following mitophagy induction. (B) Chaperone mediated autophagy degrades proteins with the pentapeptide motif KFREQ (approximately 30% of cellular proteins contain this motif). Unfolded protein is bound by hsc70, which then directly delivers protein to lysosomes for degradation via the integral protein LAMP2A.

Fig. 2

Putative pathogenic mechanisms for mitochondrial dysfunction following a loss of GCase activity. The mitochondrial dysfunction (loss of Ψm, ETC inhibition, reactive oxygen species (ROS)) observed following decreased GCase activity is most likely to be a result of inhibition of macroautophagy resulting in damaged mitochondria not being degraded by mitophagy. Inhibition of autophagic pathways also results in accumulation of α-synuclein, which can impair mitochondrial function. Dysregulation of calcium is another route by which mitochondrial function can be compromised. Increased calcium release from the ER is observed in GBA mutant cells. This in part is likely due to mutant GCase (mut) unfolding in the ER and activating ER stress. Neuroinflammation occurs in GD brains and mouse models. The production of NO by activated astrocytes and microglia will damage the mitochondrial ETC.