GBA1 mutations: Prospects for exosomal biomarkers in α-synuclein pathologies

Abstract

The discovery that patients with Gaucher Disease (GD), a rare lysosomal storage disorder, were developing symptoms similar to Parkinson's disease (PD) led to investigation of the relationship between the two seemingly unrelated pathologies. GD, an autosomal recessive disorder, is the result of a biallelic mutation in the gene GBA1, which encodes for the enzyme glucocerebrosidase (GCase). Since the observation of its relation to PD, GBA1 mutations have become recognized as the most common genetic risk factor for development of synucleinopathies such as PD and dementia with Lewy bodies. Although the exact mechanism by which GBA1 mutations promote PD is unknown, current understanding suggests that impaired GCase inhibits lysosomal activity and decreases the overall ability of the cell to degrade proteins, specifically the neuronal protein α-synuclein. Decreased elimination of α-synuclein can lead to its abnormal accumulation and aggregation, an important component of PD development. Further understanding of how decreased GCase activity increases risk for α-synuclein pathology can assist with the development of clinical biomarkers for early detection of synucleinopathies, as well as promote novel treatments tailored for people with a GBA1 mutation. Historically, α-synuclein has not been a reliable biomarker for PD. However, recent research on α-synuclein content within exosomes, which are small vesicles released by cells that carry specific cellular cargo, has yielded encouraging results. Moreover, decreased GCase activity has been shown to influence exosomal contents. Exosomes have emerged as a promising new avenue for the identification of novel biomarkers and therapeutic targets aimed at improving neuronal GCase function and limiting the development of synucleinopathies.

Keywords: Alpha-synuclein; Biomarker; Carriers; Exosomes; GBA1; Gaucher disease.

Fig. 1:. Role of GCase in α-synuclein pathology -the loss-of-function hypothesis.

1. Decreased GCase activity (shown with red X) leads to decreased degradation and accumulation of the substrates GlcCer and GlcSph. Up-regulation of GlcCer synthase also adds to the substrate load [51, 52]. 2. Decreased GCase (shown with red X) also affects the rate of total proteolysis, causing a build-up of α-synuclein [45, 48]. 3. The accumulated GlcCer and GlcSph can act as a seed for α-synuclein aggregation [45, 53]. 4. Accumulated α-synuclein increases the propensity to aggregate [54]. Evidence that has been experimentally proven in vivo is indicated with a solid arrow, while what has not yet been demonstrated is shown with a dashed arrow.

Fig. 2:. Role of GCase in α-synuclein pathology -the gain-of-function hypothesis.

A) In a wild-type cell, GCase is properly folded in the endoplasmic reticulum (ER) and successfully translocated through the Golgi into the lysosome. B) In the presence of a GBA1 mutation, the ER cannot consistently fold GCase correctly [62]. While some are appropriately configured and translocated, many are misfolded and marked for degradation. These proteins are then exported into the cytosol and degraded via the ubiquitin-proteasome system (UPS). This process is called Endoplasmic Reticulum Associated Degradation (ERAD). The gain-of-function hypothesis states that GBA1 mutations and transcription/translation of aberrant GCase greatly increases utilization of ERAD, creating and sustaining ER and UPS stress and thus impairing degradation of the total cell proteome and specifically α-synuclein oligomers [58, 66]. This can result in accumulation of these oligomers and aggregation into Lewy bodies. All evidence of this hypothesis has only been demonstrated in vitro.

Fig. 3:. Plasma exosomes as potential matrix for α-synuclein biomarker studies.

A) In normal conditions, a cell removes all waste being stored in a multi-vesicular body (MVB) by either transferring vesicles to the lysosome for degradation or exporting the vesicles via exocytosis into the CSF, at which point they are deemed exosomes [115]. These exosomes are then actively transported across the blood-brain barrier and enter the plasma [111]. B) If lysosome function is impaired, as when GBA1 mutations are present, the lysosome is not able to degrade the cellular wastes at the necessary rate [45, 47]. To compensate, the cell increases the number of vesicles that are being exported [134]. Additionally, decreased lysosomal function leads to α-synuclein accumulation, which gets re-packaged into vesicles and exported [135, 137]. These findings suggest that in the presence of lysosomal dysfunction, there is an increase in α-synuclein containing exosomes exported into the CSF, which can cross the blood-brain barrier and enter the plasma.