LAUSR

The clearance of damaged and unwanted proteins is essential for maintaining cellular homeostasis [1]. The two main mechanisms for the degradation of misfolded or aggregated proteins within the cell are the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP). Dysfunction of the UPS and ALP are seen in disorders involving protein aggregation and therefore play a critical role in common neurodegenerative diseases [2,3]. Specifically, deficits in protein clearance lead to the accumulation of α-synuclein protein in disorders known as the synucleinopathies, that include Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy [4]. Additionally, recent studies have linked deficiencies in protein clearance by the UPS and ALP with aging, further supporting the importance of protein clearance pathways in neurodegeneration. Patients with PD clinically present with bradykinesia in combination with a resting tremor, and/or rigidity. However, non-motor symptoms including depression, hyposmia and cognitive decline are also common. The neuropathological hallmark of PD is the progressive loss of dopaminergic neurons within the substantia nigra pars compacta (SNpc) and the accumulation of α-synuclein inclusions known as Lewy bodies. 5–10% of PD cases have an established monogenic cause, but over 90 different risk variants have been linked to PD in genome-wide association studies (GWAS) [5,6]. Many of the associated genes are related to the endolysosomal system or to protein clearance [7–10]. Mutations in the gene GBA1, which encodes for the lysosomal hydrolase glucocerebrosidase (GCase), are the most common genetic risk factor for PD [11]. Biallelic mutations in GBA1 result in the lysosomal storage disorder Gaucher disease (GD). GBA1 mutation carriers have a more than five-fold increased risk of developing PD. As a group, patients with GBA1associated PD (GBA1-PD) have an earlier age of onset compared to idiopathic PD and a faster disease progression [12]. An inverse relationship between decreased GCase activity and increased α-synuclein aggregation has been suggested [13]. The exact mechanisms of how GBA1 mutations cause PD remains unclear. A direct effect on ALP caused by GCase activity reduction and substrate accumulation in the lysosome has been proposed, but misfolded GCase has also been shown to cause ER stress, which initiates the unfolded protein response, affecting both the ALP and UPS. Targeting lysosomal and proteasomal dysfunction within neurodegenerative disorders has been hindered by our incomplete understanding of these processes. However, new therapies that improve protein clearance mechanisms targeting the UPS and ALP to decrease levels of protein aggregation may potentially help resolve the pathogenesis of the synucleinopathies (Figure 1). While many of these concepts can also be applied also to idiopathic forms of PD, we focus here on potential therapeutic approaches for GBA1-related PD.