Therapeutic Potential of αS Evolvability for Neuropathic Gaucher Disease

Abstract

Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by autosomal recessive mutations of the glucocerebrosidase gene, GBA1. In the majority of cases, GD has a non-neuropathic chronic form with adult onset (GD1), while other cases are more acute and severer neuropathic forms with early onset (GD2/3). Currently, no radical therapies are established for GD2/3. Notably, GD1, but not GD2/3, is associated with increased risk of Parkinson's disease (PD), the elucidation of which might provide a clue for novel therapeutic strategies. In this context, the objective of the present study is to discuss that the evolvability of α-synuclein (αS) might be differentially involved in GD subtypes. Hypothetically, aging-associated PD features with accumulation of αS, and the autophagy-lysosomal dysfunction might be an antagonistic pleiotropy phenomenon derived from αS evolvability in the development in GD1, without which neuropathies like GD2/3 might be manifested due to the autophagy-lysosomal dysfunction. Supposing that the increased severity of GD2/3 might be attributed to the decreased activity of αS evolvability, suppressing the expression of β-synuclein (βS), a potential buffer against αS evolvability, might be therapeutically efficient. Of interest, a similar view might be applicable to Niemann-Pick type C (NPC), another LSD, given that the adult type of NPC, which is comorbid with Alzheimer's disease, exhibits milder medical symptoms compared with those of infantile NPC. Thus, it is predicted that the evolvability of amyloid β and tau, might be beneficial for the adult type of NPC. Collectively, a better understanding of amyloidogenic evolvability in the pathogenesis of LSD may inform rational therapy development.

Keywords: Gaucher disease (GD); Parkinson’s disease (PD); antagonistic pleiotropy; autosomal recessive; evolvability; α-synuclein (αS); β-synuclein (βS).

Figure 1

Involvement of α-synuclein (αS) evolvability in the association of Parkinson’s disease (PD) with Gaucher disease (GD). (a) Schematics of three subtypes of GD; GD1–3. (b) A “bidirectional feedback loop” hypothesis, the most widely accepted rationale explaining the pathophysiological mechanism underlying the GD–PD association [4]. Conventionally, it was thought that accumulation of glucocerebroside (GluCer) caused by the compromised glucocerebrosidase (GCase) activity due to mutations of glucocerebrosidase (GBA) might result in stimulation of aggregation of αS, which then exacerbates lysosomal function, thus leading to formation of a vicious cycle of neurodegeneration until manifestation of PD. (c) Our amyloidogenic evolvability hypothesis; in the development/reproduction stage, αS evolvability (Evo) is lysotrophic and lysoprotective against the multiple stressors caused by autophagy-lysosomal dysfunction, and the stress information might be transgenerationally delivered to offspring. On the other hand, neurodegenerative diseases such as PD that are associated with autophagy-lysosomal dysfunction might be manifested as an antagonistic pleiotropy mechanism in aging. (d) Schematics of the differential role of αS evolvability in subtypes of GD. In GD1, αS Evo is upregulated to mitigate the multiple stressors caused by autophagy-lysosomal dysfunction in development/reproduction, but PD is later manifested through the antagonistic pleiotropy mechanism. By virtue of increased αS evolvability, GD1 is non-neuropathic. In contrast, αS Evo is suppressed in GD2/3, with GD2 being stronger than GD3. Consequently, GD2/3 are neuropathic and life expectancy is short, with GD2 being severer than GD3.

Figure 2

Dual effects of αS on lysosome activity in cells and human brain. (a) Up-regulation of lysosomal activity in cells overexpressing mutant αS [33]. Overexpression of A53TαS in B103 neuroblastoma cells resulted in increased lysosomal activity (a, g). Notably, the increase in lysosome activity appeared more prominently in mutants (P123H and V70M) βS, but not in wild type βS (b–d, g). Immunofluorescence with confocal microscopy (green: anti-αS; red: anti-βS) was performed in a-e, while cathepsin B activity was measured using fluorogenic cathepsin B substrate. Fluorogenic intensity of each time point was plotted, and the slope was calculated. Data are shown as means ± SD (n = 4). * p < 0.05, ** p < 0.01 versus vector-transfected cells. (b) Selective molecular alterations in the autophagy pathway in patients with dementia with Lewy bodies (DLB) [34]. Vibratome sections from the temporal cortex of non-demented controls and DLB patients were analyzed by immunohistochemistry. Representative sections from control and DLB brains were immunolabeled with antibodies against mTor (a, b), Atg7 (c, d), CatD (e, f), and LC3 (g, h). Semi-quantitative image analysis reveals a significant increase in mTor levels and a reduction in Atg7 levels in DLB patients compared to controls (i). Similarly, both CatD (j) and LC3 (k) immunoreactivity levels in DLB brains were significantly increased compared to those of controls. Pyramidal neurons in DLB cases show enlarged CatD-immunoreactive lysosomes (arrows). Scale bar in panel (b) represents 20 µm in all microscopy images. * p < 0.05 compared to non-demented controls in one-way ANOVA with post-hoc Dunnett’s test.

Figure 3

Therapy strategy of LSDs based on αS evolvability. (a) Diagram of the increase of αS Evo in GD2/3. If decreased Evo αS is causative for GD2/3, it is predicted that increasing αS Evo might be beneficial. Accordingly, the severity of GD2/3 neuropathy might be improved with extended life expectancy. (b) Diagram of the differential role of Aβ/tau evolvability in subtypes of NPC. In the adult type of NPC, Aβ/tau Evo is upregulated to mitigate the multiple stressors caused by autophagy-lysosomal dysfunction, but AD is later manifested through the antagonistic pleiotropy mechanism. The life expectancy of NPC (adult type) patients is shorter than that of healthy controls. In contrast, Aβ/tau Evo is suppressed in NPC (early infantile type), and life expectancy is very short. By therapeutically increasing Aβ/tau Evo, the severity of NPC (early infantile type) might be improved with extended life expectancy. (c) Therapy strategy based on αS evolvability. Since it is predicted that βS has a buffering effect on αS evolvability, αS evolvability might be increased by suppressing βS expression by ASO (Therapy: Tx).